Toll like receptor modulator compounds

ABSTRACT

This application relates generally to toll like receptor modulator compounds and pharmaceutical compositions which, among other things, modulate toll-like receptors (e.g. TLR8), and methods of making and using them.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit to U.S. Provisional ApplicationSer. No. 62/383,162, filed on Sep. 2, 2016, the disclosure of which isincorporated by reference in its entirety.

FIELD

This application relates generally to toll like receptor modulatorcompounds and pharmaceutical compositions which, among other things,modulate toll-like receptors (e.g. TLR8), and methods of making andusing them.

BACKGROUND

The toll-like receptor (TLR) family plays a fundamental role in pathogenrecognition and activation of innate immunity. Toll-like receptor 8(TLR8) is predominantly expressed by myeloid immune cells and activationof this receptor stimulates a broad immunological response. Agonists ofTLR8 activate myeloid dendritic cells, monocytes, monocyte-deriveddendridic cells and Kupffer cells leading to the production ofproinflammatory cytokines and chemokines, such as interleukin-18(IL-18), interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-α),and interferon-gamma (IFN-γ). Such agonists also promote the increasedexpression of co-stimulatory molecules such as CD8⁺ cells, majorhistocompatibility complex molecules (MAIT, NK cells), and chemokinereceptors.

Collectively, activation of these innate and adaptive immune responsesinduces an immune response and provides a therapeutic benefit in variousconditions involving autoimmunity, inflammation, allergy, asthma, graftrejection, graft versus host disease (GvHD), infection, cancer, andimmunodeficiency. For example, with respect to hepatitis B, activationof TLR8 on professional antigen presenting cells (pAPCs) and otherintrahepatic immune cells is associated with induction of IL-12 andproinflammatory cytokines, which is expected to augment HBV-specific Tcell responses, activate intrahepatic NK cells and drive reconstitutionof antiviral immunity. See e.g. Wille-Reece, U. et al. J Exp Med 203,1249-1258 (2006); Peng, G. et al., Science 309, 1380-1384 (2005); Jo, J.et al., PLoS Pathogens 10, e1004210 (2014) and Watashi, K. et al., JBiol Chem 288, 31715-31727 (2013).

Given the potential to treat a wide array of diseases, there remains aneed for novel modulators of toll like receptors, for example TLR8.Potent and selective modulators of TLR8 that have reduced potential foroff target liabilities are particularly desirable.

SUMMARY

The present disclosure provides a compound of Formula I

or a pharmaceutically acceptable salt thereof,wherein:

-   -   R¹ is —H, C₁₋₄ alkyl, or C₁₋₄ haloalkyl;    -   R² is C₁₋₆ alkyl or C₁₋₆ haloalkyl;    -   R³ is C₁₋₄ alkoxy optionally substituted with 1 R^(X);        -   each R^(X) is independently —OR^(Y), 5 to 6 membered            heterocyclyl having 1 to 3 heteroatoms selected from oxygen,            nitrogen, and sulfur optionally substituted with 1 to 3            R^(Z); phenyl optionally substituted with 1 to 3 R^(Z); or 5            to 6 membered heteroaryl having 1 to 3 heteroatoms selected            from oxygen, nitrogen, and sulfur optionally substituted            with 1 to 3 R^(Z);            -   R^(Y) is C₁₋₄ alkyl, C₁₋₄ haloalkyl, or 5 to 10 membered                heteroaryl having 1 to 3 heteroatoms selected from                oxygen, nitrogen, and sulfur optionally substituted with                1 to 3 R^(Z);    -   Q is N, CH, or CR⁴;    -   or R³ and R⁴ are taken together to form C₅₋₆ cycloalkyl; 5 to 6        membered heterocyclyl having 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered        heteroaryl having 1 to 3 heteroatoms selected from oxygen,        nitrogen, and sulfur, wherein:        -   C₅₋₆ cycloalkyl and phenyl are each independently optionally            substituted with 1 to 3 R⁵;            -   each R⁵ is independently halogen, —OH, —NH₂, —CN, C₁₋₄                alkyl optionally substituted with 1 to 3 R^(Z), C₁₋₄                haloalkyl, C₁₋₄ alkoxy, —C(O)OH, —C(O)C₁₋₄ alkyl,                —C(O)OC₁₋₄ alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl),                —C(O)N(C₁₋₄ alkyl)₂, —N(H)C(O)C₁₋₄ alkyl, —S(O)₂C₁₋₄                alkyl, or 5 to 6 membered heteroaryl having 1 to 3                heteroatoms selected from oxygen, nitrogen, and sulfur                optionally substituted with 1 to 3 R^(Z);        -   5 to 6 membered heteroaryl is optionally substituted with 1            to 3 R⁶;            -   each R⁶ is independently halogen, —OH, —NH₂, —CN, C₁₋₄                alkyl optionally substituted with 1 phenyl optionally                substituted with 1 to 3 R^(Z); C₁₋₄ haloalkyl, C₁₋₄                alkoxy, —S(O)₂C₁₋₄ alkyl; 5 to 6 membered heterocyclyl                having 1 to 3 heteroatoms selected from oxygen,                nitrogen, and sulfur optionally substituted with 1 to 3                R^(Z); phenyl optionally substituted with 1 to 3 R^(Z);                or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms                selected from oxygen, nitrogen, and sulfur optionally                substituted with 1 to 3 R^(Z);        -   5 to 6 membered heterocyclyl is optionally substituted with            1 to 3 R⁷            -   R⁷ is halogen, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, or —C(O)R⁸;                -   each R⁸ is independently C₁₋₄ alkyl optionally                    substituted with —CN or —NH₂; C₁₋₄ haloalkyl; C₅₋₆                    cycloalkyl, 5 to 6 membered heterocyclyl having 1 to                    3 heteroatoms selected from oxygen, nitrogen, and                    sulfur optionally substituted with 1 to 3 R^(Z); or                    5 to 10 membered heteroaryl having 1 to 3                    heteroatoms selected from oxygen, nitrogen, and                    sulfur optionally substituted with 1 to 3 R^(Z);                -   and        -   each R^(Z) is independently —NH₂, C₁₋₄ alkyl, halogen, —CN,            —OC₁₋₄ alkyl, C₁₋₄ haloalkyl, or —C(O)NH₂;    -   with the proviso that Formula I is not

In certain embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the pharmaceuticalcomposition comprises one or more additional therapeutic agents.

In certain embodiments, a method of modulating TLR8 is provided,comprising administering a compound of the present disclosure, or apharmaceutically acceptable salt thereof, to an individual (e.g. ahuman).

In certain embodiments, a method of treating or preventing a disease orcondition responsive to the modulation of TLR8 is provided, comprisingadministering to an individual (e.g. a human) in need thereof atherapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof. In certainembodiments, the method of treating or preventing a disease or conditionresponsive to the modulation of TLR8, comprises administering one ormore additional therapeutic agents.

In certain embodiments, a method of treating or preventing a viralinfection is provided, comprising administering to an individual (e.g. ahuman) in need thereof a therapeutically effective amount a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method of treating or preventing a hepatitis Bviral infection is provided, comprising administering to an individual(e.g. a human) in need thereof a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof. In certain embodiments, the method of treating orpreventing a hepatitis B viral infection comprises administering one ormore additional therapeutic agents. In certain embodiments, theindividual is a human infected with hepatitis B.

In certain embodiments, a method of treating or preventing a HIVinfection is provided, comprising administering to an individual (e.g. ahuman) in thereof a therapeutically effective amount a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof. Incertain embodiments, the method of treating or preventing a HIVinfection comprises administering one or more additional therapeuticagents. In certain embodiments, the individual is a human infected withHIV (e.g. HIV-1).

In certain embodiments, a method of treating a hyperproliferativedisease (e.g. cancer) is provided, comprising administering to anindividual (e.g. a human) in thereof a therapeutically effective amounta compound of the present disclosure, or a pharmaceutically acceptablesalt thereof. In certain embodiments, the method of treating ahyperproliferative disease (e.g. cancer) comprises administering one ormore additional therapeutic agents. In certain embodiments, theindividual is a human.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in medical therapy isprovided.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in treating orpreventing a disease or condition responsive to the modulation of TLR8,is provided. In certain embodiments, the disease or condition is a viralinfection.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in treating orpreventing hepatitis B, is provided

In certain embodiments, the use of a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating or preventing a disease or condition responsiveto the modulation of TLR8, is provided.

In certain embodiments, the use of a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating or preventing hepatitis B, is provided.

Kits comprising the compounds, or pharmaceutically acceptable saltsthereof, or pharmaceutical compositions of the foregoing are alsoprovided. Articles of manufacture comprising a unit dose of thecompounds, or pharmaceutically acceptable salts thereof, of theforegoing are also provided. Methods of preparing compounds of thepresent disclosure are also provided.

DETAILED DESCRIPTION

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

I. DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. A dash at the front or end of a chemical group is a matter ofconvenience to indicate the point of attachment to a parent moiety;chemical groups may be depicted with or without one or more dasheswithout losing their ordinary meaning. A prefix such as “C_(u-v),” or(C_(u)-C_(v)) indicates that the following group has from u to v carbonatoms, where u and v are integers. For example, “C₁₋₆alkyl” indicatesthat the alkyl group has from 1 to 6 carbon atoms.

“Alkyl” is a linear or branched saturated monovalent hydrocarbon. Forexample, an alkyl group can have 1 to 10 carbon atoms (i.e.,(C₁₋₁₀)alkyl) or 1 to 8 carbon atoms (i.e., (C₁₋₈)alkyl) or 1 to 6carbon atoms (i.e., (C₁₋₆ alkyl) or 1 to 4 carbon atoms (i.e.,(C₁₋₄)alkyl). Examples of alkyl groups include, but are not limited to,methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

The term “halo” or “halogen” as used herein refers to fluoro (—F),chloro (—Cl), bromo (—Br) and iodo (—I).

The term “haloalkyl” as used herein refers to an alkyl as definedherein, wherein one or more hydrogen atoms of the alkyl areindependently replaced by a halo substituent, which may be the same ordifferent. For example, C₁₋₈haloalkyl is a C₁₋₈alkyl wherein one or moreof the hydrogen atoms of the C₁₋₈alkyl have been replaced by a halosubstituent. Examples of haloalkyl groups include but are not limited tofluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbonatoms. Aryl includes a phenyl radical. Aryl also includes multiplecondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings)having about 9 to 20 carbon atoms in which at least one ring is aromaticand wherein the other rings may be aromatic or not aromatic (i.e.,carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis also to be understood that when reference is made to a certainatom-range membered aryl (e.g., 6-10 membered aryl), the atom range isfor the total ring atoms of the aryl. For example, a 6-membered arylwould include phenyl and a 10-membered aryl would include naphthyl and1, 2, 3, 4-tetrahydronaphthyl. Non-limiting examples of aryl groupsinclude, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3,4-tetrahydronaphthyl, anthracenyl, and the like.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (toform for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (toform for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form forexample indazolyl) to form the multiple condensed ring system. Thus, aheteroaryl (a single aromatic ring or multiple condensed ring system)has about 1-20 carbon atoms and about 1-6 heteroatoms within theheteroaryl ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the condensed ring. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the individual rings of the multiple condensedring system may be connected in any order relative to one another. It isto be understood that the point of attachment for a heteroaryl orheteroaryl multiple condensed ring system can be at any suitable atom ofthe heteroaryl or heteroaryl multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). It also to beunderstood that when a reference is made to a certain atom-rangemembered heteroaryl (e.g., a 5 to 10 membered heteroaryl), the atomrange is for the total ring atoms of the heteroaryl and includes carbonatoms and heteroatoms. For example, a 5-membered heteroaryl wouldinclude a thiazolyl and a 10-membered heteroaryl would include aquinolinyl. Exemplary heteroaryls include but are not limited topyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl,thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl,benzoxazolyl, indazolyl, quinoxalyl, quinazolyl,5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl,thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one,triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

The term “cycloalkyl” refers to a single saturated or partiallyunsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e.,C₃₋₂₀ cycloalkyl), for example from 3 to 12 annular atoms, for examplefrom 3 to 10 annular atoms. The term “cycloalkyl” also includes multiplecondensed, saturated and partially unsaturated all carbon ring systems(e.g., ring systems comprising 2, 3 or 4 carbocyclic rings).Accordingly, cycloalkyl includes multicyclic carbocyles such as abicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12annular carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic andtetracyclic carbocycles with up to about 20 annular carbon atoms). Therings of a multiple condensed ring system can be connected to each othervia fused, spiro and bridged bonds when allowed by valency requirements.Non-limiting examples of monocyclic cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and1-cyclohex-3-enyl.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated non-aromatic ring or anon-aromatic multiple ring system that has at least one heteroatom inthe ring (i.e., at least one annular heteroatom selected from oxygen,nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl grouphas from 5 to about 20 annular atoms, for example from 3 to 12 annularatoms, for example from 5 to 10 annular atoms. Thus, the term includessingle saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or7-membered rings) having from about 1 to 6 annular carbon atoms and fromabout 1 to 3 annular heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur in the ring. The rings of the multiplecondensed ring system can be connected to each other via fused, spiroand bridged bonds when allowed by valency requirements. Heterocyclesinclude, but are not limited to, azetidine, aziridine, imidazolidine,morpholine, oxirane (epoxide), oxetane, piperazine, piperidine,pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran,tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine,N-bromopyrrolidine, N-chloropiperidine, and the like.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results. For purposes of the present disclosure,beneficial or desired results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomand/or preventing a worsening of a symptom associated with a disease orcondition. In one embodiment, “treatment” or “treating” includes one ormore of the following: a) inhibiting the disease or condition (e.g.,decreasing one or more symptoms resulting from the disease or condition,and/or diminishing the extent of the disease or condition); b) slowingor arresting the development of one or more symptoms associated with thedisease or condition (e.g., stabilizing the disease or condition,delaying the worsening or progression of the disease or condition); andc) relieving the disease or condition, e.g., causing the regression ofclinical symptoms, ameliorating the disease state, delaying theprogression of the disease, increasing the quality of life, and/orprolonging survival.

A “compound of the present disclosure” includes compounds disclosedherein, for example a compound of the present disclosure includescompounds of Formula (I), (II), (III), and the compounds listed inTable 1. A compound of the present disclosure also includes compounds ofFormula (I), (II), (III), the compounds of Examples 1-14, and thecompounds listed in Tables 1. A compound of the present disclosure alsoincludes the compounds of Examples 1-14

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of AIDS is a method that reduces the probability ofdisease development in a given time frame and/or reduces extent of thedisease in a given time frame, when compared to not using the method.Such comparisons may be based on clinical studies, using a statisticallysignificant number of subjects. For example, the development of AIDS canbe detected using known methods, such as confirming an individual's HIV⁺status and assessing the individual's T-cell count or other indicationof AIDS development, such as extreme fatigue, weight loss, persistentdiarrhea, high fever, swollen lymph nodes in the neck, armpits or groin,or presence of an opportunistic condition that is known to be associatedwith AIDS (e.g., a condition that is generally not present inindividuals with functioning immune systems but does occur in AIDSpatients). Development may also refer to disease progression that may beinitially undetectable and includes occurrence, recurrence and onset.

As used herein, “prevention” or “preventing” refers to a regimen thatprotects against the onset of the disease or disorder such that theclinical symptoms of the disease do not develop. Thus, “prevention”relates to administration of a therapy (e.g., administration of atherapeutic substance) to a subject before signs of the disease aredetectable in the subject (e.g., administration of a therapeuticsubstance to a subject in the absence of detectable infectious agent(e.g., virus) in the subject). The subject may be an individual at riskof developing the disease or disorder, such as an individual who has oneor more risk factors known to be associated with development or onset ofthe disease or disorder. Thus, in certain embodiments, the term“preventing HBV infection” refers to administering to a subject who doesnot have a detectable HBV infection an anti-HBV therapeutic substance.It is understood that the subject for anti-HBV preventative therapy maybe an individual at risk of contracting the HBV virus. Thus, in certainembodiments, the term “preventing HIV infection” refers to administeringto a subject who does not have a detectable HIV infection an anti-HIVtherapeutic substance. It is understood that the subject for anti-HIVpreventative therapy may be an individual at risk of contracting the HIVvirus.

As used herein, an “at risk” individual is an individual who is at riskof developing a condition to be treated. An individual “at risk” may ormay not have detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment of methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). For example, individuals at risk for AIDSare those having HIV.

As used herein, the term “therapeutically effective amount” or“effective amount” refers to an amount that is effective to elicit thedesired biological or medical response, including the amount of acompound that, when administered to a subject for treating a disease, issufficient to effect such treatment for the disease. The effectiveamount will vary depending on the compound, the disease, and itsseverity and the age, weight, etc., of the subject to be treated. Theeffective amount can include a range of amounts. As is understood in theart, an effective amount may be in one or more doses, i.e., a singledose or multiple doses may be required to achieve the desired treatmentendpoint. An effective amount may be considered in the context ofadministering one or more therapeutic agents, and a single agent may beconsidered to be given in an effective amount if, in conjunction withone or more other agents, a desirable or beneficial result may be or isachieved. Suitable doses of any co-administered compounds may optionallybe lowered due to the combined action (e.g., additive or synergisticeffects) of the compounds.

As used herein, an “agonist” is a substance that stimulates its bindingpartner, typically a receptor. Stimulation is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Stimulation may be defined with respect to anincrease in a particular effect or function that is induced byinteraction of the agonist or partial agonist with a binding partner andcan include allosteric effects.

As used herein, an “antagonist” is a substance that inhibits its bindingpartner, typically a receptor. Inhibition is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Inhibition may be defined with respect to adecrease in a particular effect or function that is induced byinteraction of the antagonist with a binding partner, and can includeallosteric effects.

As used herein, a “partial agonist” or a “partial antagonist” is asubstance that provides a level of stimulation or inhibition,respectively, to its binding partner that is not fully or completelyagonistic or antagonistic, respectively. It will be recognized thatstimulation, and hence, inhibition is defined intrinsically for anysubstance or category of substances to be defined as agonists,antagonists, or partial agonists.

As used herein, “intrinsic activity” or “efficacy” relates to somemeasure of biological effectiveness of the binding partner complex. Withregard to receptor pharmacology, the context in which intrinsic activityor efficacy should be defined will depend on the context of the bindingpartner (e.g., receptor/ligand) complex and the consideration of anactivity relevant to a particular biological outcome. For example, insome circumstances, intrinsic activity may vary depending on theparticular second messenger system involved. Where such contextuallyspecific evaluations are relevant, and how they might be relevant in thecontext of the present disclosure, will be apparent to one of ordinaryskill in the art.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domestic animals

As used herein, modulation of a receptor includes agonism, partialagonism, antagonism, partial antagonism, or inverse agonism of areceptor.

The nomenclature used herein to name the subject compounds isillustrated in the Examples and elsewhere herein.

As used herein, “co-administration” includes administration of unitdosages of the compounds disclosed herein before or after administrationof unit dosages of one or more additional therapeutic agents, forexample, administration of the compound disclosed herein within seconds,minutes, or hours of the administration of one or more additionaltherapeutic agents. For example, in some embodiments, a unit dose of acompound of the present disclosure is administered first, followedwithin seconds or minutes by administration of a unit dose of one ormore additional therapeutic agents. Alternatively, in other embodiments,a unit dose of one or more additional therapeutic agents is administeredfirst, followed by administration of a unit dose of a compound of thepresent disclosure within seconds or minutes. In some embodiments, aunit dose of a compound of the present disclosure is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of one or more additional therapeutic agents. In otherembodiments, a unit dose of one or more additional therapeutic agents isadministered first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of a compound of the presentdisclosure.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The compounds of described herein may be prepared and/or formulated aspharmaceutically acceptable salts. Pharmaceutically acceptable salts arenon-toxic salts of a free base form of a compound that possesses thedesired pharmacological activity of the free base. These salts may bederived from inorganic or organic acids or bases. For example, acompound that contains a basic nitrogen may be prepared as apharmaceutically acceptable salt by contacting the compound with aninorganic or organic acid. Non-limiting examples of pharmaceuticallyacceptable salts include sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, methylsulfonates, propylsulfonates, besylates,xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists ofother suitable pharmaceutically acceptable salts are found in Remington:The Science and Practice of Pharmacy, 21^(st) Edition, LippincottWiliams and Wilkins, Philadelphia, Pa., 2006.

Examples of “pharmaceutically acceptable salts” of the compoundsdisclosed herein also include salts derived from an appropriate base,such as an alkali metal (for example, sodium, potassium), an alkalineearth metal (for example, magnesium), ammonium and NX₄ ⁺ (wherein X isC₁-C₄ alkyl). Also included are base addition salts, such as sodium orpotassium salts.

Provided are also compounds described herein or pharmaceuticallyacceptable salts, isomers, or a mixture thereof, in which from 1 to nhydrogen atoms attached to a carbon atom may be replaced by a deuteriumatom or D, in which n is the number of hydrogen atoms in the molecule.As known in the art, the deuterium atom is a non-radioactive isotope ofthe hydrogen atom. Such compounds may increase resistance to metabolism,and thus may be useful for increasing the half-life of the compoundsdescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof when administered to a mammal. See, e.g., Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”, TrendsPharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized bymeans well known in the art, for example by employing starting materialsin which one or more hydrogen atoms have been replaced by deuterium.

Examples of isotopes that can be incorporated into the disclosedcompounds also include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. Substitution with positron emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds of Formula (I), can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.The present disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,for example, chromatography and fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centres of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Wherecompounds are represented in their chiral form, it is understood thatthe embodiment encompasses, but is not limited to, the specificdiastereomerically or enantiomerically enriched form. Where chirality isnot specified but is present, it is understood that the embodiment isdirected to either the specific diastereomerically or enantiomericallyenriched form; or a racemic or scalemic mixture of such compound(s). Asused herein, “scalemic mixture” is a mixture of stereoisomers at a ratioother than 1:1.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present disclosure contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are non-superimposablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present disclosure includestautomers of any said compounds.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

The term “prodrug” is defined in the pharmaceutical field as abiologically inactive derivative of a drug that upon administration tothe human body is converted to the biologically active parent drugaccording to some chemical or enzymatic pathway.

The terms “combination antiretroviral therapy” (“cART”) refers tocombinations or “cocktails” of antiretroviral medications used to treathuman viral infections, including HIV infections. As used herein, theterms “combination antiretroviral therapy” and “cART includecombinations and regimens often referred to as Highly ActiveAntiretroviral Therapy (HAART). HAART and cART combinations and regimenscommonly include multiple, often two or more, drugs such as nucleosidereverse transcriptase inhibitors (NRTIs), non-nucleoside reversetranscriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusioninhibitors, CCR5 agonists, and/or integrase inhibitors.

The terms “latent HIV reservoir”, “HIV latent reservoir”, “HIVreservoir”, “latent reservoir”, and “latent HIV infection” refer to acondition in which resting CD4+ T lymphocytes or other cells areinfected with HIV but are not actively producing HIV. The presentlyinactive HIV infected cells are referred to as “latently infectedcells”. Antiretroviral therapy (ART) can reduce the level of HIV in theblood to an undetectable level, while latent reservoirs of HIV continueto survive. When a latently infected cell is reactivated, the cellbegins to produce HIV (HIV replication).

II. COMPOUNDS

The present disclosure provides a compound of Formula I

or a pharmaceutically acceptable salt thereof,wherein:

-   -   R¹ is —H, C₁₋₄ alkyl, or C₁₋₄ haloalkyl;    -   R² is C₁₋₆ alkyl or C₁₋₆ haloalkyl;    -   R³ is C₁₋₄ alkoxy optionally substituted with 1 R^(X);        -   each R^(X) is independently —OR^(Y), 5 to 6 membered            heterocyclyl having 1 to 3 heteroatoms selected from oxygen,            nitrogen, and sulfur optionally substituted with 1 to 3            R^(Z); phenyl optionally substituted with 1 to 3 R^(Z); or 5            to 6 membered heteroaryl having 1 to 3 heteroatoms selected            from oxygen, nitrogen, and sulfur optionally substituted            with 1 to 3 R^(Z);            -   R^(Y) is C₁₋₄ alkyl, C₁₋₄ haloalkyl, or 5 to 10 membered                heteroaryl having 1 to 3 heteroatoms selected from                oxygen, nitrogen, and sulfur optionally substituted with                1 to 3 R^(Z);    -   Q is N, CH, or CR⁴;    -   or R³ and R⁴ are taken together to form C₅₋₆ cycloalkyl; 5 to 6        membered heterocyclyl having 1 to 3 heteroatoms selected from        oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 membered        heteroaryl having 1 to 3 heteroatoms selected from oxygen,        nitrogen, and sulfur, wherein:        -   C₅₋₆ cycloalkyl and phenyl are each independently optionally            substituted with 1 to 3 R⁵;            -   each R⁵ is independently halogen, —OH, —NH₂, —CN, C₁₋₄                alkyl optionally substituted with 1 to 3 R^(Z), C₁₋₄                haloalkyl, C₁₋₄ alkoxy, —C(O)OH, —C(O)C₁₋₄ alkyl,                —C(O)OC₁₋₄ alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl),                —C(O)N(C₁₋₄ alkyl)₂, —N(H)C(O)C₁₋₄ alkyl, —S(O)₂C₁₋₄                alkyl, or 5 to 6 membered heteroaryl having 1 to 3                heteroatoms selected from oxygen, nitrogen, and sulfur                optionally substituted with 1 to 3 R^(Z);        -   5 to 6 membered heteroaryl is optionally substituted with 1            to 3 R⁶;            -   each R⁶ is independently halogen, —OH, —NH₂, —CN, C₁₋₄                alkyl optionally substituted with 1 phenyl optionally                substituted with 1 to 3 R^(Z); C₁₋₄ haloalkyl, C₁₋₄                alkoxy, —S(O)₂C₁₋₄ alkyl; 5 to 6 membered heterocyclyl                having 1 to 3 heteroatoms selected from oxygen,                nitrogen, and sulfur optionally substituted with 1 to 3                R^(Z); phenyl optionally substituted with 1 to 3 R^(Z);                or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms                selected from oxygen, nitrogen, and sulfur optionally                substituted with 1 to 3 R^(Z);        -   5 to 6 membered heterocyclyl is optionally substituted with            1 to 3 R⁷            -   R⁷ is halogen, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, or —C(O)R⁸;                each R⁸ is independently C₁₋₄ alkyl optionally                substituted with —CN or —NH₂; C₁₋₄ haloalkyl; C₅₋₆                cycloalkyl, 5 to 6 membered heterocyclyl having 1 to 3                heteroatoms selected from oxygen, nitrogen, and sulfur                optionally substituted with 1 to 3 R^(Z); or 5 to 10                membered heteroaryl having 1 to 3 heteroatoms selected                from oxygen, nitrogen, and sulfur optionally substituted                with 1 to 3 R^(Z);            -   and        -   each R^(Z) is independently —NH₂, C₁₋₄ alkyl, halogen, —CN,            —OC₁₋₄ alkyl, C₁₋₄ haloalkyl, or —C(O)NH₂;    -   with the proviso that Formula I is not

In certain embodiments of Formula (I), Q is N, CH, or CR⁴. In certainembodiments of Formula (I), Q is N. In certain embodiments of Formula(I), Q is CH. In certain embodiments of Formula (I), Q is CR⁴. Incertain embodiments of Formula (I), Q is CH or CR⁴.

In certain embodiments of Formula (I), R¹ is —H, C₁₋₄ alkyl, or C₁₋₄haloalkyl. In certain embodiments of Formula (I), R¹ is —H or C₁₋₄alkyl. In certain embodiments of Formula (I), R¹ is methyl. In certainembodiments of Formula (I), R¹ is ethyl. In certain embodiments ofFormula (I), R¹ is propyl. In certain embodiments of Formula (I), R¹ istrifluoromethyl.

In certain embodiments of Formula (I), R² is C₁₋₆ alkyl or C₁₋₆haloalkyl. In certain embodiments of Formula (I), R² is C₃₋₆ alkyl. Incertain embodiments of Formula (I), R² is methyl. In certain embodimentsof Formula (I), R² is ethyl. In certain embodiments of Formula (I), R²is propyl. In certain embodiments of Formula (I), R² is butyl. Incertain embodiments of Formula (I), R² is pentyl. In certain embodimentsof Formula (I), R² is hexyl.

In certain embodiments of Formula (I), R¹ is —H or C₁₋₄ alkyl; R² isC₃₋₆ alkyl; Q is CR⁴; R³ and R⁴ are taken together to form C₅₋₆cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatomsselected from oxygen, nitrogen, and sulfur; phenyl; or 5 to 6 memberedheteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, andsulfur, wherein: phenyl is optionally substituted with 1 to 3 halogen; 5to 6 membered heteroaryl is optionally substituted with 1 to 3 R⁶; eachR⁶ is independently halogen, —OH, C₁₋₄ alkyl, or C₁₋₄ alkoxy; and 5 to 6membered heterocyclyl is optionally substituted with 1 to 3 —C(O)C₁₋₄alkyl.

In certain embodiments of Formula (I), R¹ is —H or C₁₋₄ alkyl; R² isC₃₋₆ alkyl; R³ and R⁴ are taken together to form C₅₋₆ cycloalkyl; 5 to 6membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen,nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein phenylis optionally substituted with 1 to 3 halogen; 5 to 6 memberedheteroaryl is optionally substituted with 1 to 3 R⁶; each R⁶ isindependently halogen, —OH, C₁₋₄ alkyl, or C₁₋₄ alkoxy; and 5 to 6membered heterocyclyl is optionally substituted with 1 to 3 —C(O)R⁸wherein each R⁸ is independently C₁₋₄ alkyl optionally substituted with—CN or —NH₂, C₁₋₃ haloalkyl, cyclopropyl, cyclobutyl, tetrahydropyranyl,thienyl optionally substituted with 1 to 3 C₁₋₃ alkyl; thiazolyl,imidazolyl optionally substituted with 1 to 3 C₁₋₂ alkyl; oxazolyl,isoxazolyl optionally substituted with 1 to 3 C₁₋₂ alkyl; thiadiazolyl,phenyl, pyrazinyl, or quinolinyl.

In certain embodiments of Formula (I), R¹ is —H or C₁₋₄ alkyl; R² isC₃₋₆ alkyl; R³ and R⁴ are taken together to form C₅₋₆ cycloalkyl; 5 to 6membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen,nitrogen, and sulfur; phenyl; or 5 to 6 membered heteroaryl having 1 to3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein phenylis optionally substituted with 1 to 3 halogen; 5 to 6 memberedheteroaryl is optionally substituted with 1 to 3 R⁶; each R⁶ isindependently halogen, —OH, C₁₋₄ alkyl, or C₁₋₄ alkoxy; and 5 to 6membered heterocyclyl is optionally substituted with 1 to 3 —C(O)C₁₋₄alkyl.

In certain embodiments of Formula (I), (II), or (III), R³ is C₁₋₄ alkoxyoptionally substituted with 1 to 3 R^(X), wherein R^(X) is defined inthis application. In certain embodiments of Formula (I), (II), or (III),R³ is C₁₋₄ alkoxy optionally substituted with 1 R^(X), wherein R^(X) isdefined in this application. In certain embodiments of Formula (I),(II), or (III), R³ is C₁₋₂ alkoxy optionally substituted with 1 to 3R^(X), wherein R^(X) is defined in this application.

In certain embodiments of Formula (I), (II), or (III), each R^(X) isindependently —OR^(Y), 5 to 6 membered heterocyclyl having 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur optionallysubstituted with 1 to 3 R^(Z); phenyl optionally substituted with 1 to 3R^(Z); or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selectedfrom oxygen, nitrogen, and sulfur optionally substituted with 1 to 3R^(Z), wherein R^(Y) and R^(Z) are defined in this application. Incertain embodiments of Formula (I), (II), or (III), each R^(X) isindependently OR^(Y), morpholino, phenyl, pyridinyl, pyrazolyl, orpyridazinyl, wherein each morpholino, phenyl, pyridinyl, pyrazolyl, andpyridazinyl are independently optionally substituted with —OCH₃, C₁₋₃alkyl, chloro, or fluoro; wherein R^(Y) is —CH₃, —CH₂CF₃, or quinolinyloptionally substituted with —OCH₃, C₁₋₃ alkyl, chloro, or fluoro.

In certain embodiments of Formula (I), (II), or (III), each R^(Y) isindependently C₁₋₄ alkyl, C₁₋₄ haloalkyl, or 5 to 10 membered heteroarylhaving 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfuroptionally substituted with 1 to 3 R^(Z) wherein R^(Z) is defined inthis application. In certain embodiments of Formula (I), (II), or (III),each R^(Y) is independently R^(Y) is —CH₃, —CH₂CF₃, or quinolinyloptionally substituted with —OCH₃, C₁₋₃ alkyl, chloro, or fluoro.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form C₅₋₆ cycloalkyl; 5 to 6 membered heterocyclylhaving 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selectedfrom oxygen, nitrogen, and sulfur, wherein C₅₋₆ cycloalkyl and phenylare each independently optionally substituted with 1 to 3 R⁵; 5 to 6membered heteroaryl is optionally substituted with 1 to 3 R⁶; 5 to 6membered heterocyclyl is optionally substituted with 1 to 3 R⁷; whereinR⁵, R⁶, and R⁷ are defined in this application.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form C₅₋₆ cycloalkyl optionally substituted with 1 to3 R⁵, wherein R⁵ is defined in this application. In certain embodimentsof Formula (I), (II), or (III), R³ and R⁴ are taken together to formC₅₋₆ cycloalkyl. In certain embodiments of Formula (I), (II), or (III),R³ and R⁴ are taken together to form a 6 membered cycloalkyl.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form a 5 to 6 membered heterocyclyl having 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur optionallysubstituted with 1 to 3 R⁷, wherein R⁷ is defined in this application.In certain embodiments of Formula (I), (II), or (III), each R⁷ is—C(O)R⁸ wherein R⁸ is C₁₋₄ alkyl optionally substituted with —CN or—NH₂, C₁₋₃ haloalkyl, cyclopropyl, cyclobutyl, tetrahydropyranyl,thienyl optionally substituted with 1 to 3 C₁₋₃ alkyl; thiazolyl,imidazolyl optionally substituted with 1 to 3 C₁₋₂ alkyl; oxazolyl,isoxazolyl optionally substituted with 1 to 3 C₁₋₂ alkyl; thiadiazolyl,phenyl, pyrazinyl, or quinolinyl. In certain embodiments of Formula (I),(II), or (III), R⁷ is —C(O)C₁₋₄alkyl. In certain embodiments of Formula(I), (II), or (III), R⁷ is —C(O)CH₃. In certain embodiments of Formula(I), (II), or (III), R³ and R⁴ are taken together to form atetrahydropyridinyl optionally substituted with —C(O)R⁸ wherein R⁸ isC₁₋₄ alkyl optionally substituted with —CN or —NH₂, C₁₋₃ haloalkyl,cyclopropyl, cyclobutyl, tetrahydropyranyl, thienyl optionallysubstituted with 1 to 3 C₁₋₃ alkyl; thiazolyl, imidazolyl optionallysubstituted with 1 to 3 C₁₋₂ alkyl; oxazolyl, isoxazolyl optionallysubstituted with 1 to 3 C₁₋₂ alkyl; thiadiazolyl, phenyl, pyrazinyl, orquinolinyl.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form a phenyl optionally substituted with 1 to 3 R⁵,wherein R⁵ is defined in this application. In certain embodiments ofFormula (I), (II), or (III), R³ and R⁴ are taken together to form aphenyl. In certain embodiments of Formula (I), (II), or (III), R³ and R⁴are taken together to form a phenyl optionally substituted with 1 to 3chloro, fluoro, bromo, —CN, C₁₋₂ alkyl optionally substituted with —OH,C₁₋₂ alkoxy, —C(O)C₁₋₂ alkyl, —C(O)OC₁₋₂ alkyl, or pyrazolyl optionallysubstituted with 1 to 3 C₁₋₂ alkyl; or imidazolyl optionally substitutedwith 1 to 3 C₁₋₂ alkyl.

In certain embodiments of Formula (I), (II), or (III), each R⁵ isindependently halogen, —OH, —NH₂, —CN, C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₄alkoxy, —C(O)OH, —C(O)C₁₋₄ alkyl, —C(O)OC₁₋₄ alkyl, —C(O)NH₂,—C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄ alkyl)₂, —N(H)C(O)C₁₋₄ alkyl,—S(O)₂C₁₋₄ alkyl. In certain embodiments of Formula (I), (II), or (III),each R⁵ is independently chloro, fluoro, bromo, —CN, C₁₋₂ alkyloptionally substituted with —OH, C₁₋₂ alkoxy, —C(O)C₁₋₂ alkyl,—C(O)OC₁₋₂ alkyl, or pyrazolyl optionally substituted with 1 to 3 C₁₋₂alkyl; or imidazolyl optionally substituted with 1 to 3 C₁₋₂ alkyl. Incertain embodiments of Formula (I), (II), or (III), each R⁵ isindependently chloro, fluoro, bromo, —CN, —CH₃, —CF₃, —OCH₃, —C(O)CH₃,or —C(O)OCH₃. In certain embodiments of Formula (I), (II), or (III),each R⁵ is independently chloro, fluoro, bromo, —CN, —CH₃, —OCH₃,—C(O)CH₃, or —C(O)OCH₃.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form a 5 to 6 membered heteroaryl having 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur optionallysubstituted with 1 to 3 R⁶, wherein R⁶ is defined in the application. Incertain embodiments of Formula (I), (II), or (III), each R⁶ isindependently halogen, —OH, C₁₋₄ alkyl, or C₁₋₄ alkoxy. In certainembodiments of Formula (I), (II), or (III), each R⁶ is independentlyhalogen, —OH, —CH₃, or —OCH₃. In certain embodiments of Formula (I),(II), or (III), R³ and R⁴ are taken together to form a 5 to 6 memberedheteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, andsulfur. In certain embodiments of Formula (I), (II), or (III), R³ and R⁴are taken together to form pyrazinyl, pyridinyl or thienyl optionallysubstituted with 1 to 3 C₁₋₂ alkyl.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein each R⁵, R⁶, or R⁷ is optionally present and as defined herein.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (II)

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form a 6 membered cycloalkyl. In certainembodiments of a compound of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form tetrahydropyridinyl optionally substituted with 1to 3 C(O)C₁₋₂ alkyl. In certain embodiments of a compound of Formula(I), (II), or (III), R³ and R⁴ are taken together to form phenyloptionally substituted with 1 to 3 fluoro. In certain embodiments of acompound of Formula (I), (II), or (III), R³ and R⁴ are taken together toform pyrazinyl, thienyl or pyridinyl.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form phenyl optionally substituted with 1to 3 chloro, fluoro, bromo, —CN, C₁₋₂ alkyl optionally substituted with—OH, C₁₋₂ alkoxy, —C(O)C₁₋₂ alkyl, or —C(O)OC₁₋₂ alkyl.

In certain embodiments of a compound of Formula (II), R³ and R⁴ aretaken together to form:

wherein each R⁵, R⁶, or R⁷ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), the compound is acompound of Formula (III)

The groups R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(X), R^(Y), and R^(Z) are asdefined for Formula (I) above, or as defined below, or any combinationthereof. Accordingly, in certain embodiments of Formula (I), (II), or(III), R³ is C₁₋₄ alkoxy optionally substituted with 1 to 3 R^(X),wherein R^(X) is defined in this application. Accordingly, in certainembodiments of Formula (I), (II), or (III), R³ is C₁₋₄ alkoxy optionallysubstituted with 1 R^(X), wherein R^(X) is defined in this application.In certain embodiments of Formula (I), (II), or (III), R³ is C₁₋₂ alkoxyoptionally substituted with 1 to 3 R^(X), wherein R^(X) is defined inthis application.

In certain embodiments of Formula (I), (II), or (III), each R^(X) isindependently —OR^(Y), 5 to 6 membered heterocyclyl having 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur optionallysubstituted with 1 to 3 R^(Z); phenyl optionally substituted with 1 to 3R^(Z); or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selectedfrom oxygen, nitrogen, and sulfur optionally substituted with 1 to 3R^(Z), wherein R^(Y) and R^(Z) are defined in this application. Incertain embodiments of Formula (I), (II), or (III), each R^(X) isindependently OR^(Y), morpholino, phenyl, pyridinyl, pyrazolyl, orpyridazinyl, wherein each morpholino, phenyl, pyridinyl, pyrazolyl, andpyridazinyl are independently optionally substituted with —OCH₃, C₁₋₃alkyl, chloro, or fluoro; wherein R^(Y) is —CH₃, —CH₂CF₃, or quinolinyloptionally substituted with —OCH₃, C₁₋₃ alkyl, chloro, or fluoro.

In certain embodiments of Formula (I), (II), or (III), each R^(Y) isindependently C₁₋₄ alkyl, C₁₋₄ haloalkyl, or 5 to 10 membered heteroarylhaving 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfuroptionally substituted with 1 to 3 R^(Z) wherein R^(Z) is defined inthis application. In certain embodiments of Formula (I), (II), or (III),each R^(Y) is independently R^(Y) is —CH₃, —CH₂CF₃, or quinolinyloptionally substituted with —OCH₃, C₁₋₃ alkyl, chloro, or fluoro.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form C₅₋₆ cycloalkyl; 5 to 6 membered heterocyclylhaving 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur;phenyl; or 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selectedfrom oxygen, nitrogen, and sulfur, wherein C₅₋₆ cycloalkyl and phenylare each independently optionally substituted with 1 to 3 R⁵, 5 to 6membered heteroaryl is optionally substituted with 1 to 3 R⁶; 5 to 6membered heterocyclyl is optionally substituted with 1 to 3 R⁷; whereinR⁵, R⁶, and R⁷ are defined in this application.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form C₅₋₆ cycloalkyl optionally substituted with 1 to3 R⁵, wherein R⁵ is defined in this application. In certain embodimentsof Formula (I), (II), or (III), R³ and R⁴ are taken together to formC₅₋₆ cycloalkyl. In certain embodiments of Formula (I), R³ and R⁴ aretaken together to form a 6 membered cycloalkyl.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form a 5 to 6 membered heterocyclyl having 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur optionallysubstituted with 1 to 3 R⁷, wherein R⁷ is defined in this application.In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form a 5 to 6 membered heterocyclyl having 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur optionallysubstituted with 1 to 3 —C(O)R⁸ wherein R⁸ is C₁₋₄ alkyl optionallysubstituted with —CN or —NH₂, C₁₋₃ haloalkyl, cyclopropyl, cyclobutyl,tetrahydropyranyl, thienyl optionally substituted with 1 to 3 C₁₋₃alkyl; thiazolyl, imidazolyl optionally substituted with 1 to 3 C₁₋₂alkyl; oxazolyl, isoxazolyl optionally substituted with 1 to 3 C₁₋₂alkyl; thiadiazolyl, phenyl, pyrazinyl, or quinolinyl. In certainembodiments of Formula (I), (II), or (III), R³ and R⁴ are taken togetherto form a tetrahydropyridinyl optionally substituted with —C(O)R⁸wherein R⁸ is C₁₋₄ alkyl optionally substituted with —CN or —NH₂, C₁₋₃haloalkyl, cyclopropyl, cyclobutyl, tetrahydropyranyl, thienyloptionally substituted with 1 to 3 C₁₋₃ alkyl; thiazolyl, imidazolyloptionally substituted with 1 to 3 C₁₋₂ alkyl; oxazolyl, isoxazolyloptionally substituted with 1 to 3 C₁₋₂ alkyl; thiadiazolyl, phenyl,pyrazinyl, or quinolinyl.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form a phenyl optionally substituted with 1 to 3 R⁵,wherein R⁵ is defined in this application. In certain embodiments ofFormula (I), (II), or (III), R³ and R⁴ are taken together to form aphenyl. In certain embodiments of Formula (I), (II), or (III), R³ and R⁴are taken together to form a phenyl optionally substituted with 1 to 3chloro, fluoro, bromo, —CN, C₁₋₂ alkyl optionally substituted with —OH,C₁₋₂ alkoxy, —C(O)C₁₋₂ alkyl, —C(O)OC₁₋₂ alkyl, or pyrazolyl optionallysubstituted with 1 to 3 C₁₋₂ alkyl; or imidazolyl optionally substitutedwith 1 to 3 C₁₋₂ alkyl.

In certain embodiments of Formula (I), (II), or (III), R³ and R⁴ aretaken together to form a 5 to 6 membered heteroaryl having 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur optionallysubstituted with 1 to 3 R⁶, wherein R⁶ is defined in the application. Incertain embodiments of Formula (I), (II), or (III), R³ and R⁴ are takentogether to form a 5 to 6 membered heteroaryl having 1 to 3 heteroatomsselected from oxygen, nitrogen, and sulfur. In certain embodiments ofFormula (I), (II), or (III), R³ and R⁴ are taken together to formpyrazinyl, pyridinyl or thienyl optionally substituted with 1 to 3 C₁₋₂alkyl.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein each R⁵, R⁶, or R⁷ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein R⁵ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein R⁷ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein R⁷ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein R⁶ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein R⁵ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein R⁶ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein R⁶ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

wherein R⁶ is optionally present and as defined herein.

In certain embodiments of a compound of Formula (I), (II), or (III), R³and R⁴ are taken together to form:

In certain embodiments of a compound of Formula (I), (II), or (III),each R⁵ is independently halogen, —OH, —NH₂, —CN, C₁₋₄ alkyl optionallysubstituted with 1 to 3 R^(Z), C₁₋₄ haloalkyl, C₁₋₄ alkoxy, —C(O)OH,—C(O)C₁₋₄ alkyl, —C(O)OC₁₋₄ alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄ alkyl),—C(O)N(C₁₋₄ alkyl)₂, —N(H)C(O)C₁₋₄ alkyl, —S(O)₂C₁₋₄ alkyl, or 5 to 6membered heteroaryl having 1 to 3 heteroatoms selected from oxygen,nitrogen, and sulfur optionally substituted with 1 to 3 R^(Z), whereinR^(Z) is defined in this application. In certain embodiments of acompound of Formula (I), (II), or (III), each R⁵ is independentlychloro, fluoro, bromo, —CN, C₁₋₂ alkyl optionally substituted with —OH,C₁₋₂ alkoxy, —C(O)C₁₋₂ alkyl, —C(O)OC₁₋₂ alkyl, or pyrazolyl optionallysubstituted with 1 to 3 C₁₋₂ alkyl; or imidazolyl optionally substitutedwith 1 to 3 C₁₋₂ alkyl

In certain embodiments of a compound of Formula (I), (II), or (III),each R⁶ is independently halogen, —OH, —NH₂, —CN, C₁₋₄ alkyl optionallysubstituted with 1 phenyl optionally substituted with 1 to 3 R^(Z); C₁₋₄haloalkyl, C₁₋₄ alkoxy, —S(O)₂C₁₋₄ alkyl; 5 to 6 membered heterocyclylhaving 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfuroptionally substituted with 1 to 3 R^(Z); phenyl optionally substitutedwith 1 to 3 R^(Z); or 5 to 6 membered heteroaryl having 1 to 3heteroatoms selected from oxygen, nitrogen, and sulfur optionallysubstituted with 1 to 3 R^(Z), wherein R^(Z) is defined in thisapplication. In certain embodiments of a compound of Formula (I), (II),or (III), each R⁶ is independently C₁₋₂ alkyl.

In certain embodiments of a compound of Formula (I), (II), or (III),each R⁷ is independently halogen, —OH, C₁₋₄ alkyl, C₁₋₄ alkoxy, or—C(O)R⁸ wherein R⁸ is defined in this application. In certainembodiments of a compound of Formula (I), (II), or (III), each R⁷ isindependently —C(O)R⁸ wherein R⁸ is C₁₋₄ alkyl optionally substitutedwith —CN or —NH₂; C₁₋₃ haloalkyl, cyclopropyl, cyclobutyl,tetrahydropyranyl, thienyl optionally substituted with 1 to 3 C₁₋₃alkyl; thiazolyl, imidazolyl optionally substituted with 1 to 3 C₁₋₂alkyl; oxazolyl, isoxazolyl optionally substituted with 1 to 3 C₁₋₂alkyl; thiadiazolyl, phenyl, pyrazinyl, or quinolinyl.

In certain embodiments of a compound of Formula (I), (II), or (III),each R⁸ is independently C₁₋₄ alkyl optionally substituted with —CN or—NH₂; C₁₋₄ haloalkyl; C₅₋₆ cycloalkyl, 5 to 6 membered heterocyclylhaving 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfuroptionally substituted with 1 to 3 R^(Z); or 5 to 10 membered heteroarylhaving 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfuroptionally substituted with 1 to 3 R^(Z), wherein R^(Z) is defined inthis application. In certain embodiments of a compound of Formula (I),(II), or (III), each R⁸ is independently C₁₋₄ alkyl optionallysubstituted with —CN or —NH₂, C₁₋₃ haloalkyl, cyclopropyl, cyclobutyl,tetrahydropyranyl, thienyl optionally substituted with 1 to 3 C₁₋₃alkyl; thiazolyl, imidazolyl optionally substituted with 1 to 3 C₁₋₂alkyl; oxazolyl, isoxazolyl optionally substituted with 1 to 3 C₁₋₂alkyl; thiadiazolyl, phenyl, pyrazinyl, or quinolinyl

In certain embodiments of a compound of Formula (I), (II), or (III),each R^(Z) is independently —NH₂, C₁₋₄ alkyl, halogen, —CN, —OC₁₋₄alkyl, C₁₋₄ haloalkyl, or —C(O)NH₂.

In certain embodiments, the compound of Formula (I) is selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (II) is selected from:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (III) is selected from:

or a pharmaceutically acceptable salt thereof.

As used herein, “a compound of Formula (I)” includes compounds forFormula (II), or (III).

III. COMPOSITIONS

In certain embodiments, the present disclosure provides a pharmaceuticalcomposition comprising a compound of the present disclosure (e.g. acompound of Formula (I), (II), or (III), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, the pharmaceutical composition comprises one ormore additional therapeutic agent, as more fully set forth below.

Pharmaceutical compositions comprising the compounds disclosed herein,or pharmaceutically acceptable salts thereof, may be prepared with oneor more pharmaceutically acceptable excipients which may be selected inaccord with ordinary practice. Tablets may contain excipients includingglidants, fillers, binders and the like. Aqueous compositions may beprepared in sterile form, and when intended for delivery by other thanoral administration generally may be isotonic. All compositions mayoptionally contain excipients such as those set forth in the Rowe et al,Handbook of Pharmaceutical Excipients, 6^(th) edition, AmericanPharmacists Association, 2009. Excipients can include ascorbic acid andother antioxidants, chelating agents such as EDTA, carbohydrates such asdextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearicacid and the like. In certain embodiments, the composition is providedas a solid dosage form, including a solid oral dosage form.

The compositions include those suitable for various administrationroutes, including oral administration. The compositions may be presentedin unit dosage form and may be prepared by any of the methods well knownin the art of pharmacy. Such methods include the step of bringing intoassociation the active ingredient (e.g., a compound of the presentdisclosure or a pharmaceutical salt thereof) with one or morepharmaceutically acceptable excipients. The compositions may be preparedby uniformly and intimately bringing into association the activeingredient with liquid excipients or finely divided solid excipients orboth, and then, if necessary, shaping the product. Techniques andformulations generally are found in Remington: The Science and Practiceof Pharmacy, 21^(st) Edition, Lippincott Wiliams and Wilkins,Philadelphia, Pa., 2006.

Compositions described herein that are suitable for oral administrationmay be presented as discrete units (a unit dosage form) including butnot limited to capsules, cachets or tablets each containing apredetermined amount of the active ingredient. In one embodiment, thepharmaceutical composition is a tablet.

Pharmaceutical compositions disclosed herein comprise one or morecompounds disclosed herein, or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable excipient andoptionally other therapeutic agents. Pharmaceutical compositionscontaining the active ingredient may be in any form suitable for theintended method of administration. When used for oral use for example,tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, syrups or elixirsmay be prepared. Compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore excipients including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipients which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,lactose monohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

The amount of active ingredient that may be combined with the inactiveingredients to produce a dosage form may vary depending upon theintended treatment subject and the particular mode of administration.For example, in some embodiments, a dosage form for oral administrationto humans may contain approximately 1 to 1000 mg of active materialformulated with an appropriate and convenient amount of apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutically acceptable excipient varies from about 5 to about 95%of the total compositions (weight:weight).

In certain embodiments, a composition comprising a compound of thepresent disclosure (e.g. a compound of Formula (I), (II), or (III), or apharmaceutically acceptable salt thereof in one variation does notcontain an agent that affects the rate at which the active ingredient ismetabolized. Thus, it is understood that compositions comprising acompound of the present disclosure in one aspect do not comprise anagent that would affect (e.g., slow, hinder or retard) the metabolism ofa compound of the present disclosure or any other active ingredientadministered separately, sequentially or simultaneously with a compoundof the present disclosure. It is also understood that any of themethods, kits, articles of manufacture and the like detailed herein inone aspect do not comprise an agent that would affect (e.g., slow,hinder or retard) the metabolism of a compound of the present disclosureor any other active ingredient administered separately, sequentially orsimultaneously with a compound of the present disclosure.

IV. METHODS

The present disclosure provides for methods of treating diseases orconditions that are responsive to the modulation of toll-like receptors(e.g. TLR8 receptors). While not wishing to be bound by any one theory,the presently disclosed compounds are believed to modulate TLR8receptors as agonists. As is understood by those of skill in the art,modulators of TLR8 may, to some degree, modulate other toll-likereceptors (e.g. TLR7). As such, in certain embodiments, the compoundsdisclosed herein may also modulate TLR7 to a measurable degree. Incertain embodiments, those compounds that modulate TLR8 to a higherdegree than TLR7 are considered selective modulators of TLR8. Exemplarymethods of measuring the each compounds respective modulation of TLR7and TLR8 are described in the Examples provided herein. In certainembodiments, the compounds disclosed herein are selective modulators ofTLR8.

In certain embodiments, a method of modulating TLR8 is provided,comprising administering a compound of the present disclosure, or apharmaceutically acceptable salt thereof, to an individual (e.g. ahuman).

In certain embodiments, a method of modulating TLR8 in vitro isprovided.

In certain embodiments, the present disclosure provides a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,for use as a research tool, e.g., for use in identifying modulators ofTLR8

In certain embodiments, the present disclosure provides methods for thetreatment or prevention of diseases or conditions in an individual (e.g.a human) in need thereof, comprising administering a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof. Incertain embodiments, the methods comprise administering one or moreadditional therapeutic agents. Treatment with a compound of the presentdisclosure typically results in the stimulation of an immune response tothe particular disease or condition being treated. Diseases orconditions contemplated by the present disclosure include those affectedby the modulation of toll-like receptors (e.g. TLR8). In certainembodiments, a method of treating or preventing a disease or conditionresponsive to the modulation of TLR8 is provided, comprisingadministering to a human a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof. Exemplary diseases, disorders and conditions include butare not limited to conditions involving autoimmunity, inflammation,allergy, asthma, graft rejection, graft versus host disease (GvHD),infectious diseases, cancer, and immunodeficiency.

In certain embodiments, infectious diseases include diseases such ashepatitis A, hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV),HIV, human papillomavirus (HPV), respiratory syncytial virus (RSV),severe acute respiratory syndrome (SARS), influenza, parainfluenza,cytomegalovirus, dengue, herpes simplex virus-1, herpes simplex virus-2,leishmania infection, and respiratory syncytial virus. In certainembodiments, infectious diseases include diseases such as hepatitis A,hepatitis B (HBV), hepatitis D (HDV), HIV, human papillomavirus (HPV),respiratory syncytial virus (RSV), severe acute respiratory syndrome(SARS), influenza, parainfluenza, cytomegalovirus, dengue, herpessimplex virus-1, herpes simplex virus-2, leishmania infection, andrespiratory syncytial virus.

In certain embodiments, a method of treating or preventing a viralinfection is provided, comprising administering to an individual (e.g. ahuman) a therapeutically effective amount a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof. In oneembodiment, the method can be used to induce an immune response againstmultiple epitopes of a viral infection in a human. Induction of animmune response against viral infection can be assessed using anytechnique that is known by those of skill in the art for determiningwhether an immune response has occurred. Suitable methods of detectingan immune response for the present disclosure include, among others,detecting a decrease in viral load or antigen in a subject's serum,detection of IFN-gamma-secreting peptide specific T cells, and detectionof elevated levels of one or more liver enzymes, such as alaninetransferase (ALT) and aspartate transferase (AST). In one embodiment,the detection of IFN-gamma-secreting peptide specific T cells isaccomplished using an ELISPOT assay. Another embodiment includesreducing the viral load associated with HBV infection, including areduction as measured by PCR testing.

In certain embodiments, the present invention provides a method forenhancing the efficacy of a vaccine by co-administering with thevaccine, a therapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, to anindividual (e.g. a human). In certain embodiments, the compound of thepresent disclosure or a pharmaceutically acceptable salt thereof, may beco-administered with a vaccine to boost the immune response by allowingthe production of a higher amount of antibodies or by allowing a longerlasting protection. In certain embodiments, the compounds of the presentdisclosure, or a pharmaceutically acceptable salt thereof, may be usedas vaccine adjuvants to increase the efficacy and response to theimmunization with a particular antigen. In certain embodiments,co-administering the compounds of the present disclosure, or apharmaceutically acceptable salt thereof, with a vaccine, may influencethe way a vaccine's antigen is presented to the immune system andenhance the vaccine's efficacy.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, for use in medical therapy isprovided. In certain embodiments, a compound of the present disclosureor a pharmaceutically acceptable salt thereof, for use in treating orpreventing a disease or condition responsive to the modulation of TLR8,is provided. In certain embodiments, the disease or condition is a viralinfection as set forth herein.

In certain embodiments, the use of a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for treating or preventing a disease or condition responsiveto the modulation of TLR8, is provided.

In certain embodiments, the present disclosure also provides methods fortreating a hepatitis B viral infection, comprising administering to anindividual (e.g. a human) infected with hepatitis B virus atherapeutically effective amount a compound of the present disclosure ora pharmaceutically acceptable salt thereof. Typically, the individual issuffering from a chronic hepatitis B infection, although it is withinthe scope of the present disclosure to treat people who are acutelyinfected with HBV.

The present disclosure also provides methods for treating a hepatitis Cviral infection, comprising administering to an individual (e.g. ahuman) infected with hepatitis C virus a therapeutically effectiveamount a compound of the present disclosure or a pharmaceuticallyacceptable salt thereof. Typically, the individual is suffering from achronic hepatitis C infection, although it is within the scope of thepresent disclosure to treat people who are acutely infected with HCV.

Treatment of HBV or HCV in accordance with the present disclosuretypically results in the stimulation of an immune response against HBVor HCV in an individual (e.g. a human) being infected with HBV or HCV,respectively, and a consequent reduction in the viral load of HBV or HCVin the infected individual. Examples of immune responses includeproduction of antibodies (e.g., IgG antibodies) and/or production ofcytokines, such as interferons, that modulate the activity of the immunesystem. The immune system response can be a newly induced response, orcan be boosting of an existing immune response. In particular, theimmune system response can be seroconversion against one or more HBV orHCV antigens.

As described more fully herein, compounds of the present disclosure canbe administered with one or more additional therapeutic agent(s) to anindividual (e.g. a human) infected with HBV or HCV. The additionaltherapeutic agent(s) can be administered to the infected individual(e.g. a human) at the same time as a compound of the present disclosureor before or after administration of a compound of the presentdisclosure. For example, in certain embodiments, when used to treat orprevent HCV, a compound of the present disclosure may be administeredwith one or more additional therapeutic agent(s) selected from the groupconsisting of interferons, ribavirin or its analogs, HCV NS3 proteaseinhibitors, HCV NS4 protease inhibitors, HCV NS3/NS4 proteaseinhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,nucleoside or nucleotide inhibitors of HCV NS5B polymerase,non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors,TLR7 agonists, cyclophilin inhibitors, HCV IRES inhibitors,pharmacokinetic enhancers, and other drugs for treating HCV, or mixturesthereof. Specific examples are more fully described below.

Further, in certain embodiments, when used to treat or prevent HBV, acompound of the present disclosure may be administered with one or moreadditional therapeutic agent(s) selected from the group consisting ofHBV DNA polymerase inhibitors, toll-like receptor 7 modulators,toll-like receptor 8 modulators, Toll-like receptor 7 and 8 modulators,Toll-like receptor 3 modulators, interferon alpha ligands, HBsAginhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBVtherapeutic vaccines, HBV prophylactic vaccines, HBV viral entryinhibitors, NTCP inhibitors, antisense oligonucleotide targeting viralmRNA, short interfering RNAs (siRNA), hepatitis B virus E antigeninhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies includingHBV antibodies targeting the surface antigens of the hepatitis B virus,thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core orcapsid protein inhibitors), stimulators of retinoic acid-inducible gene1, stimulators of NOD2, recombinant thymosin alpha-1 and hepatitis Bvirus replication inhibitors, and combinations thereof. Specificexamples are more fully described below.

In certain embodiments, the present disclosure provides a method forameliorating a symptom associated with an HBV infection or HCVinfection, wherein the method comprises administering to an individual(e.g. a human) infected with hepatitis B virus or hepatitis C virus atherapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, wherein thetherapeutically effective amount is sufficient to ameliorate a symptomassociated with the HBV infection or HCV infection. Such symptomsinclude the presence of HBV virus particles (or HCV virus particles) inthe blood, liver inflammation, jaundice, muscle aches, weakness andtiredness.

In certain embodiments, the present disclosure provides a method forreducing the rate of progression of a hepatitis B viral infection or ahepatitis C virus infection, in an individual (e.g. a human), whereinthe method comprises administering to an individual (e.g. a human)infected with hepatitis B virus or hepatitis C virus a therapeuticallyeffective amount of a compound of the present disclosure, or apharmaceutically acceptable salt thereof, wherein the therapeuticallyeffective amount is sufficient to reduce the rate of progression of thehepatitis B viral infection or hepatitis C viral infection. The rate ofprogression of the infection can be followed by measuring the amount ofHBV virus particles or HCV virus particles in the blood.

In certain embodiments, the present disclosure provides a method forreducing the viral load associated with HBV infection or HCV infection,wherein the method comprises administering to an individual (e.g. ahuman) infected with HBV or HCV a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, wherein the therapeutically effective amount is sufficientto reduce the HBV viral load or the HCV viral load in the individual.

In certain embodiments, the present disclosure provides a method ofinducing or boosting an immune response against hepatitis B virus orhepatitis C virus in an individual (e.g. a human), wherein the methodcomprises administering a therapeutically effective amount of a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, to the individual, wherein a new immune response againsthepatitis B virus or hepatitis C virus is induced in the individual, ora preexisting immune response against hepatitis B virus or hepatitis Cvirus is boosted in the individual. Seroconversion with respect to HBVor HCV can be induced in the individual. Examples of immune responsesinclude production of antibodies, such as IgG antibody molecules, and/orproduction of cytokine molecules that modulate the activity of one ormore components of the human immune system.

In certain embodiments, an immune response can be induced against one ormore antigens of HBV or HCV. For example, an immune response can beinduced against the HBV surface antigen (HBsAg), or against the smallform of the HBV surface antigen (small S antigen), or against the mediumform of the HBV surface antigen (medium S antigen), or against acombination thereof. Again by way of example, an immune response can beinduced against the HBV surface antigen (HBsAg) and also against otherHBV-derived antigens, such as the core polymerase or x-protein.

Induction of an immune response against HCV or HBV can be assessed usingany technique that is known by those of skill in the art for determiningwhether an immune response has occurred. Suitable methods of detectingan immune response for the present disclosure include, among others,detecting a decrease in viral load in a individual's serum, such as bymeasuring the amount of HBV DNA or HCV DNA in a subject's blood using aPCR assay, and/or by measuring the amount of anti-HBV antibodies, oranti-HCV antibodies, in the subject's blood using a method such as anELISA.

In certain embodiments, a compound of a compound of the presentdisclosure (e.g. a compound of Formula (I)), or a pharmaceuticallyacceptable salt thereof, for use in treating or preventing a HBVinfection is provided. In certain embodiments, a compound of the presentdisclosure (e.g. a compound of Formula (I)), or a pharmaceuticallyacceptable salt thereof, for use in treating or preventing a HCVinfection is provided. In certain embodiments, a compound of the presentdisclosure (e.g. a compound of Formula (I)), or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament fortreating or preventing a HBV infection is provided. In certainembodiments, a compound of the present disclosure (e.g. a compound ofFormula (I)), or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for treating or preventing a HCV infectionis provided.

In certain embodiments, the present disclosure also provides methods fortreating a Retroviridae viral infection (e.g., an HIV viral infection)in an individual (e.g., a human), comprising administering a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,to the individual.

In certain embodiments, the present disclosure also provides methods fortreating a HIV infection (e.g a HIV-1 infection), comprisingadministering to an individual (e.g. a human) infected with HIV virus atherapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof. In certainembodiments, the individual in need thereof is a human who has beeninfected with HIV. In certain embodiments, the individual in needthereof is a human who has been infected with HIV but who has notdeveloped AIDS. In certain embodiments, the individual in need thereofis an individual at risk for developing AIDS. In certain embodiments,the individual in need thereof is a human who has been infected with HIVand who has developed AIDS.

In certain embodiments, a method for treating or preventing an HIV viralinfection in an individual (e.g., a human), comprising administering acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, to the individual is provided.

In certain embodiments, a method for inhibiting the replication of theHIV virus, treating AIDS or delaying the onset of AIDS in an individual(e.g., a human), comprising administering a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, to theindividual is provided.

In certain embodiments, a method for preventing an HIV infection in anindividual (e.g., a human), comprising administering a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, tothe individual is provided. In certain embodiments, the individual is atrisk of contracting the HIV virus, such as an individual who has one ormore risk factors known to be associated with of contracting the HIVvirus.

In certain embodiments, a method for treating an HIV infection in anindividual (e.g., a human), comprising administering a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, tothe individual is provided.

In certain embodiments, a method for treating an HIV infection in anindividual (e.g., a human), comprising administering to the individualin need thereof a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and other drugs fortreating HIV, and combinations thereof is provided.

In certain embodiments, a compound of the present invention isadministered to a patient where active HIV gene expression has beensuppressed by administration of antiretroviral therapy (includingcombination antiretroviral therapy” or “cART”).

In certain embodiments, a method of reducing the latent HIV reservoir ina human infected with HIV is provided, the method comprisingadministering to the human a pharmaceutically effective amount of acompound of the present disclosure. In certain embodiments, the methodfurther comprises administering one or more anti-HIV agents. In certainembodiments, the method further comprises administering antiretroviraltherapy (including combination antiretroviral therapy” or “cART”). Incertain embodiments, active HIV gene expression in the human has beensuppressed by administration of antiretroviral therapy (includingcombination antiretroviral therapy” or “cART”).

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof for use in medical therapy ofan HIV viral infection (e.g. HIV-1 or the replication of the HIV virus(e.g. HIV-1) or AIDS or delaying the onset of AIDS in an individual(e.g., a human)) is provided.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof for use in the manufacture of amedicament for treating an HIV viral infection or the replication of theHIV virus or AIDS or delaying the onset of AIDS in an individual (e.g.,a human). One embodiment provides a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, for use in theprophylactic or therapeutic treatment of an HIV infection or AIDS or foruse in the therapeutic treatment or delaying the onset of AIDS isprovided.

In certain embodiments, the use of a compound of the present disclosure(e.g. a compound of Formula (I)), or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for an HIV virus infectionin an individual (e.g., a human) is provided. In certain embodiments, acompound of the present disclosure (e.g. a compound of Formula (I)), ora pharmaceutically acceptable salt thereof, for use in the prophylacticor therapeutic treatment of an HIV virus infection is provided.

In certain embodiments, in the methods of use, the administration is toan individual (e.g., a human) in need of the treatment. In certainembodiments, in the methods of use, the administration is to anindividual (e.g., a human) who is at risk of developing AIDS.

Provided herein is a compound of the present disclosure (e.g. a compoundof Formula (I)), or a pharmaceutically acceptable salt thereof, for usein therapy. In one embodiment, the compound of the present disclosure,or a pharmaceutically acceptable salt thereof, is for use in a method oftreating an HIV viral infection or the replication of the HIV virus orAIDS or delaying the onset of AIDS in an individual (e.g., a human).

Also provided herein is a compound of the present disclosure (e.g. acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in a method of treating or preventing HIV in an individual inneed thereof. In certain embodiments, the individual in need thereof isa human who has been infected with HIV. In certain embodiments, theindividual in need thereof is a human who has been infected with HIV butwho has not developed AIDS. In certain embodiments, the individual inneed thereof is an individual at risk for developing AIDS. In certainembodiments, the individual in need thereof is a human who has beeninfected with HIV and who has developed AIDS.

Also provided herein is a compound of the present disclosure (e.g. acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in the therapeutic treatment or delaying the onset of AIDS.

Also provided herein is a compound of the present disclosure (e.g. acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in the prophylactic or therapeutic treatment of an HIVinfection.

In certain embodiments, the HIV infection is an HIV-1 infection.

Additionally, the compounds of this disclosure are useful in thetreatment of cancer or tumors (including dysplasias, such as uterinedysplasia). These includes hematological malignancies, oral carcinomas(for example of the lip, tongue or pharynx), digestive organs (forexample esophagus, stomach, small intestine, colon, large intestine, orrectum), peritoneum, liver and biliary passages, pancreas, respiratorysystem such as larynx or lung (small cell and non-small cell), bone,connective tissue, skin (e.g., melanoma), breast, reproductive organs(fallopian tube, uterus, cervix, testicles, ovary, or prostate), urinarytract (e.g., bladder or kidney), brain and endocrine glands such as thethyroid. In summary, the compounds of this disclosure are employed totreat any neoplasm, including not only hematologic malignancies but alsosolid tumors of all kinds. In certain embodiments, the compounds areuseful for treating a form of cancer selected from ovarian cancer,breast cancer, head and neck cancer, renal cancer, bladder cancer,hepatocellular cancer, and colorectal cancer.

Hematological malignancies are broadly defined as proliferativedisorders of blood cells and/or their progenitors, in which these cellsproliferate in an uncontrolled manner. Anatomically, the hematologicmalignancies are divided into two primary groups: lymphomas—malignantmasses of lymphoid cells, primarily but not exclusively in lymph nodes,and leukemias—neoplasm derived typically from lymphoid or myeloid cellsand primarily affecting the bone marrow and peripheral blood. Thelymphomas can be sub-divided into Hodgkin's Disease and Non-Hodgkin'slymphoma (NHL). The later group comprises several distinct entities,which can be distinguished clinically (e.g. aggressive lymphoma,indolent lymphoma), histologically (e.g. follicular lymphoma, mantlecell lymphoma) or based on the origin of the malignant cell (e.g. Blymphocyte, T lymphocyte). Leukemias and related malignancies includeacute myelogenous leukemia (AML), chronic myelogenous leukemia (CML),acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia(CLL). Other hematological malignancies include the plasma celldyscrasias including multiple myeloma, and the myelodysplasticsyndromes.

In certain embodiments, the compounds of the present disclosure areuseful in the treatment of B-cell lymphoma, lymphoplasmacytoid lymphoma,fallopian tube cancer, head and neck cancer, ovarian cancer, andperitoneal cancer.

In certain embodiments, the compounds of the present disclosure areuseful in the treatment of hepatocellular carcinoma, gastric cancer,and/or colorectal cancer. In certain embodiments, the compounds of thepresent disclosure are useful in the treatment of prostate cancer,breast cancer, and/or ovarian cancer. In certain embodiments, thecompounds of the present disclosure are useful in the treatment ofrecurrent or metastatic squamous cell carcinoma.

In certain embodiments, a method of treating a hyperproliferativedisease, comprising administering to an individual (e.g. a human) inneed thereof a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isprovided. In certain embodiments, the hyperproliferative disease iscancer. In certain embodiments, the cancer is a solid tumor. In certainembodiments, the cancer is selected from ovarian cancer, breast cancer,head and neck cancer, renal cancer, bladder cancer, hepatocellularcancer, and colorectal cancer. In certain embodiments, the cancer is alymphoma. In certain embodiments, the cancer is Hodgkin's lymphoma. Incertain embodiments, the cancer is non-Hodgkin's lymphoma. In certainembodiments, the cancer is B-cell lymphoma. In certain embodiments, thecancer is selected from B-cell lymphoma; fallopian tube cancer, head andneck cancer, ovarian cancer and peritoneal cancer. In certainembodiments, the method further comprises administering one or moreadditional therapeutic agents as more fully described herein.

In certain embodiments, the cancer is prostate cancer, breast cancer,ovarian cancer, hepatocellular carcinoma, gastric cancer, colorectalcancer and/or recurrent or metastatic squamous cell carcinoma. Incertain embodiments, the cancer is prostate cancer, breast cancer,and/or ovarian cancer. In certain embodiments, the cancer ishepatocellular carcinoma, gastric cancer, and/or colorectal cancer. Incertain embodiments, the cancer is recurrent or metastatic squamous cellcarcinoma.

In some embodiments, in the methods of use, the administration is to anindividual (e.g., a human) in need of the treatment.

Additional examples of diseases, disorders, or conditions includepsoriasis, systemic lupus erythematosus and allergic rhinitis

In one embodiment, the compound of the present disclosure, or apharmaceutically acceptable salt thereof, is for use in a method oftreating a hyperproliferative disease (e.g. cancer) in an individual(e.g., a human).

Also provided herein is the use of a compound of the present disclosure(e.g. a compound of Formula (I)) or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for treating ahyperproliferative disease (e.g. cancer) is provided.

V. ADMINISTRATION

One or more of the compounds of the present disclosure (also referred toherein as the active ingredients), can be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, rectal, nasal, topical (including buccal and sublingual),transdermal, vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. It will be appreciated that the preferred route may vary withfor example the condition of the recipient. An advantage of certaincompounds disclosed herein is that they are orally bioavailable and canbe dosed orally.

A compound of the present disclosure, such as a compound of Formula (I),may be administered to an individual in accordance with an effectivedosing regimen for a desired period of time or duration, such as atleast about one month, at least about 2 months, at least about 3 months,at least about 6 months, or at least about 12 months or longer. In onevariation, the compound is administered on a daily or intermittentschedule for the duration of the individual's life.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compound may be administered to an individual (e.g., a human) in aneffective amount. In certain embodiments, the compound is administeredonce daily.

In certain embodiments, methods for treating or preventing a disease orcondition in a human are provided, comprising administering to the humana therapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or more(e.g., one, two, three, four, one or two, one to three, or one to four)additional therapeutic agents. As modulators of TLR8 may be used in thetreatment of various diseases or conditions, the particular identity ofthe additional therapeutic agents will depend on the particular diseaseor condition being treated.

The compound of Formula (I), (II), or (III) can be administered by anyuseful route and means, such as by oral or parenteral (e.g.,intravenous) administration. Therapeutically effective amounts of thecompound of Formula (I), (II), or (III) are from about 0.00001 mg/kgbody weight per day to about 10 mg/kg body weight per day, such as fromabout 0.0001 mg/kg body weight per day to about 10 mg/kg body weight perday, or such as from about 0.001 mg/kg body weight per day to about 1mg/kg body weight per day, or such as from about 0.01 mg/kg body weightper day to about 1 mg/kg body weight per day, or such as from about 0.05mg/kg body weight per day to about 0.5 mg/kg body weight per day, orsuch as from about 0.3 μg to about 30 mg per day, or such as from about30 μg to about 300 μg per day.

A compound of the present disclosure may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound ofthe present disclosure (e.g., from 1 mg to 1000 mg of compound).Therapeutically effective amounts of the compound of Formula (I), (II),or (III) are from about 0.01 mg per dose to about 1000 mg per dose, suchas from about 0.01 mg per dose to about 100 mg per dose, or such as fromabout 0.1 mg per dose to about 100 mg per dose, or such as from about 1mg per dose to about 100 mg per dose, or such as from about 1 mg perdose to about 10 mg per dose. Other therapeutically effective amounts ofthe compound of Formula (I), (II), or (III) are about 1 mg per dose, orabout 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55,60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Othertherapeutically effective amounts of the compound of Formula (I), (II),or (III) are about 100 mg per dose, or about 125, 150, 175, 200, 225,250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dosecan be administered hourly, daily, or weekly. For example, a single dosecan be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or onceevery 24 hours. A single dose can also be administered once every 1 day,2, 3, 4, 5, 6, or once every 7 days. A single dose can also beadministered once every 1 week, 2, 3, or once every 4 weeks. In certainembodiments, a single dose can be administered once every week. A singledose can also be administered once every month.

The frequency of dosage of the compound of Formula (I), (II), or (III)will be determined by the needs of the individual patient and can be,for example, once per day or twice, or more times, per day.Administration of the compound continues for as long as necessary totreat the HBV or HCV infection. For example, Compound I can beadministered to a human being infected with HBV or HCV for a period offrom 20 days to 180 days or, for example, for a period of from 20 daysto 90 days or, for example, for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound ofFormula (I), (II), or (III) followed by a period of several or more daysduring which a patient does not receive a daily dose of the compound.For example, a patient can receive a dose of the compound every otherday, or three times per week. Again by way of example, a patient canreceive a dose of the compound each day for a period of from 1 to 14days, followed by a period of 7 to 21 days during which the patient doesnot receive a dose of the compound, followed by a subsequent period(e.g., from 1 to 14 days) during which the patient again receives adaily dose of the compound. Alternating periods of administration of thecompound, followed by non-administration of the compound, can berepeated as clinically required to treat the patient.

In one embodiment, pharmaceutical compositions comprising a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,in combination with one or more (e.g., one, two, three, four, one ortwo, one to three, or one to four) additional therapeutic agents, and apharmaceutically acceptable excipient are provided.

In one embodiment, kits comprising a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, in combination with oneor more (e.g., one, two, three, four, one or two, one to three, or oneto four) additional therapeutic agents are provided.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In certain embodiments, when a compound of the present disclosure iscombined with one or more additional therapeutic agents as describedherein, the components of the composition are administered as asimultaneous or sequential regimen. When administered sequentially, thecombination may be administered in two or more administrations.

In certain embodiments, a compound of the present disclosure is combinedwith one or more additional therapeutic agents in a unitary dosage formfor simultaneous administration to a patient, for example as a soliddosage form for oral administration.

In certain embodiments, a compound of the present disclosure isadministered with one or more additional therapeutic agents.Co-administration of a compound of the present disclosure with one ormore additional therapeutic agents generally refers to simultaneous orsequential administration of a compound of the present disclosure andone or more additional therapeutic agents, such that therapeuticallyeffective amounts of the compound disclosed herein and one or moreadditional therapeutic agents are both present in the body of thepatient.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents, for example,administration of the compound disclosed herein within seconds, minutes,or hours of the administration of one or more additional therapeuticagents. For example, in some embodiments, a unit dose of a compound ofthe present disclosure is administered first, followed within seconds orminutes by administration of a unit dose of one or more additionaltherapeutic agents. Alternatively, in other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed by administration of a unit dose of a compound of the presentdisclosure within seconds or minutes. In some embodiments, a unit doseof a compound of the present disclosure is administered first, followed,after a period of hours (e.g., 1-12 hours), by administration of a unitdose of one or more additional therapeutic agents. In other embodiments,a unit dose of one or more additional therapeutic agents is administeredfirst, followed, after a period of hours (e.g., 1-12 hours), byadministration of a unit dose of a compound of the present disclosure.

VI. COMBINATION THERAPY FOR HBV

In certain embodiments, a method for treating or preventing an HBVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, four, one or two, one tothree, or one to four) additional therapeutic agents. In one embodiment,a method for treating an HBV infection in a human having or at risk ofhaving the infection is provided, comprising administering to the humana therapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,four, one or two, one to three, or one to four) additional therapeuticagents.

In certain embodiments, the present disclosure provides a method fortreating an HBV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents which are suitable for treating an HBV infection.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four, or more additional therapeutic agents. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four, or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

Administration of HBV Combination Therapy

In certain embodiments, when a compound disclosed herein is combinedwith one or more additional therapeutic agents as described above, thecomponents of the composition are administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations.

Co-administration of a compound disclosed herein with one or moreadditional therapeutic agents generally refers to simultaneous orsequential administration of a compound disclosed herein and one or moreadditional therapeutic agents, such that therapeutically effectiveamounts of each agent are present in the body of the patient.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents. The compounddisclosed herein may be administered within seconds, minutes, or hoursof the administration of one or more additional therapeutic agents. Forexample, in some embodiments, a unit dose of a compound disclosed hereinis administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents. Alternatively, in other embodiments, a unit dose of one or moreadditional therapeutic agents is administered first, followed byadministration of a unit dose of a compound disclosed herein withinseconds or minutes. In some embodiments, a unit dose of a compounddisclosed herein is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of one ormore additional therapeutic agents. In other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound disclosed herein.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments a compound of Formula (I) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HBV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HBV.

In certain embodiments, such tablets are suitable for once daily dosing.

HBV Combination Therapy

In the above embodiments, the additional therapeutic agent may be ananti-HBV agent. For example, the additional therapeutic agent may beselected from the group consisting of HBV combination drugs, other drugsfor treating HBV, 3-dioxygenase (IDO) inhibitors, antisenseoligonucleotide targeting viral mRNA, Apolipoprotein A1 modulator,arginase inhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton'styrosine kinase (BTK) inhibitors, CCR2 chemokine antagonist, CD137inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonist andmodulator, compounds targeting HBcAg, compounds targeting hepatitis Bcore antigen (HBcAg), covalently closed circular DNA (cccDNA)inhibitors, cyclophilin inhibitors, cytokines, cytotoxicT-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymeraseinhibitor, Endonuclease modulator, epigenetic modifiers, Farnesoid Xreceptor agonist, gene modifiers or editors, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, HBV antibodies, HBV DNA polymeraseinhibitors, HBV replication inhibitors, HBV RNAse inhibitors, HBVvaccines, HBV viral entry inhibitors, HBx inhibitors, Hepatitis B largeenvelope protein modulator, Hepatitis B large envelope proteinstimulator, Hepatitis B structural protein modulator, hepatitis Bsurface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg)secretion or assembly inhibitors, hepatitis B virus E antigeninhibitors, hepatitis B virus replication inhibitors, Hepatitis virusstructural protein inhibitor, HIV-1 reverse transcriptase inhibitor,Hyaluronidase inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,Immunoglobulin agonist, Immunoglobulin G modulator, immunomodulators,indoleamine-2, inhibitors of ribonucleotide reductase, Interferonagonist, Interferon alpha 1 ligand, Interferon alpha 2 ligand,Interferon alpha 5 ligand modulator, Interferon alpha ligand, Interferonalpha ligand modulator, interferon alpha receptor ligands, Interferonbeta ligand, Interferon ligand, Interferon receptor modulator,Interleukin-2 ligand, ipi4 inhibitors, lysine demethylase inhibitors,histone demethylase inhibitors, KDM5 inhibitors, KDM1 inhibitors, killercell lectin-like receptor subfamily G member 1 inhibitors,lymphocyte-activation gene 3 inhibitors, lymphotoxin beta receptoractivators, microRNA (miRNA) gene therapy agents, modulators of Ax1,modulators of B7-H3, modulators of B7-H4, modulators of CD160,modulators of CD161, modulators of CD27, modulators of CD47, modulatorsof CD70, modulators of GITR, modulators of HEVEM, modulators of ICOS,modulators of Mer, modulators of NKG2A, modulators of NKG2D, modulatorsof OX40, modulators of SIRPalpha, modulators of TIGIT, modulators ofTim-4, modulators of Tyro, Na+-taurocholate cotransporting polypeptide(NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2gene stimulator, Nucleoprotein inhibitor, nucleoprotein modulators, PD-1inhibitors, PD-L1 inhibitors, PEG-Interferon Lambda, Peptidylprolylisomerase inhibitor, phosphatidylinositol-3 kinase (PI3K) inhibitors,recombinant scavenger receptor A (SRA) proteins, recombinant thymosinalpha-1, Retinoic acid-inducible gene 1 stimulator, Reversetranscriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymeraseinhibitor, short interfering RNAs (siRNA), short synthetic hairpin RNAs(sshRNAs), SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinaseinhibitor, stimulator of interferon gene (STING) agonists, stimulatorsof NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surfaceglycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand,Tim-3 inhibitors, TLR3 agonist, TLR7 agonist, TLR9 agonist, TLR9 genestimulator, toll-like receptor (TLR) modulators, Viral ribonucleotidereductase inhibitor, zinc finger nucleases or synthetic nucleases(TALENs), and combinations thereof.

In certain embodiments, a compound of Formula (I) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HBV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HBV, such as 3-dioxygenase (IDO)inhibitors, Apolipoprotein A1 modulator, arginase inhibitors, B- andT-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK)inhibitors, CCR2 chemokine antagonist, CD137 inhibitors, CD160inhibitors, CD305 inhibitors, CD4 agonist and modulator, compoundstargeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg),core protein allosteric modulators, covalently closed circular DNA(cccDNA) inhibitors, cyclophilin inhibitors, cytotoxicT-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymeraseinhibitor, Endonuclease modulator, epigenetic modifiers, Famesoid Xreceptor agonist, HBsAg inhibitors, HBsAg secretion or assemblyinhibitors, HBV DNA polymerase inhibitors, HBV replication inhibitors,HBV RNAse inhibitors, HBV viral entry inhibitors, HBx inhibitors,Hepatitis B large envelope protein modulator, Hepatitis B large envelopeprotein stimulator, Hepatitis B structural protein modulator, hepatitisB surface antigen (HBsAg) inhibitors, hepatitis B surface antigen(HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigeninhibitors, hepatitis B virus replication inhibitors, Hepatitis virusstructural protein inhibitor, HIV-1 reverse transcriptase inhibitor,Hyaluronidase inhibitor, IAPs inhibitors, IL-2 agonist, IL-7 agonist,immunomodulators, indoleamine-2 inhibitors, inhibitors of ribonucleotidereductase, Interleukin-2 ligand, ipi4 inhibitors, lysine demethylaseinhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5inhibitors, killer cell lectin-like receptor subfamily G member 1inhibitors, lymphocyte-activation gene 3 inhibitors, lymphotoxin betareceptor activators, modulators of Ax1, modulators of B7-H3, modulatorsof B7-H4, modulators of CD160, modulators of CD161, modulators of CD27,modulators of CD47, modulators of CD70, modulators of GITR, modulatorsof HEVEM, modulators of ICOS, modulators of Mer, modulators of NKG2A,modulators of NKG2D, modulators of OX40, modulators of SIRPalpha,modulators of TIGIT, modulators of Tim-4, modulators of Tyro,Na+-taurocholate cotransporting polypeptide (NTCP) inhibitors, naturalkiller cell receptor 2B4 inhibitors, NOD2 gene stimulator, Nucleoproteininhibitor, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors,Peptidylprolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI3K)inhibitors, Retinoic acid-inducible gene 1 stimulator, Reversetranscriptase inhibitor, Ribonuclease inhibitor, RNA DNA polymeraseinhibitor, SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinaseinhibitor, stimulator of interferon gene (STING) agonists, stimulatorsof NOD1, T cell surface glycoprotein CD28 inhibitor, T-cell surfaceglycoprotein CD8 modulator, Thymosin agonist, Thymosin alpha 1 ligand,Tim-3 inhibitors, TLR3 agonist, TLR7 agonist, TLR9 agonist, TLR9 genestimulator, toll-like receptor (TLR) modulators, Viral ribonucleotidereductase inhibitor, and combinations thereof.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from HBVcombination drugs, HBV vaccines, HBV DNA polymerase inhibitors,immunomodulators toll-like receptor (TLR) modulators, interferon alphareceptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen(HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors,antisense oligonucleotide targeting viral mRNA, short interfering RNAs(siRNA) and ddRNAi endonuclease modulators, ribonucelotide reductaseinhibitors, HBV E antigen inhibitors, covalently closed circular DNA(cccDNA) inhibitors, famesoid X receptor agonists, HBV antibodies, CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators, retinoic acid-inducible gene 1 stimulators, NOD2stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors,indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors,PD-L1 inhibitors, recombinant thymosin alpha-1, bruton's tyrosine kinase(BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginaseinhibitors, and other HBV drugs.

HBV Combination Drugs

Examples of combination drugs for the treatment of HBV include TRUVADA®(tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine,and PEG-IFN-alpha; ABX-203adefovir, and PEG-IFNalpha; and INO-1800(INO-9112 and RG7944).

Other HBV Drugs

Examples of other drugs for the treatment of HBV includealpha-hydroxytropolones, amdoxovir, beta-hydroxycytosine nucleosides,CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicrin(gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NOV-205(molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131,levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai),rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA,cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA,Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang),MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai,IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551,and ZH-2N, and the compounds disclosed in US20150210682, (Roche), US2016/0122344 (Roche), WO2015173164, WO2016023877, US2015252057A (Roche),WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090A (Roche),WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899A (Roche),WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586A (Roche), andUS2015031687A (Roche).

HBV Vaccines

HBV vaccines include both prophylactic and therapeutic vaccines.Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim,Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M(LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L,DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylacticvaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIX B®,recombinant hepatitis B vaccine (intramuscular, Kangtai BiologicalProducts), recombinant hepatitis B vaccine (Hansenual polymorpha yeast,intramuscular, Hualan Biological Engineering), recombinant hepatitis Bsurface antigen vaccine, Bimmugen, Euforavac, Eutravac,anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, PentabioVaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, InfanrixHep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, HeberbiovacHB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene,SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf,Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine, andDTaP-rHB-Hib vaccine.

Examples of HBV therapeutic vaccines include HBsAG-HBIG complex,ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay,GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC(NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2,CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500,HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine,HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine(HBV infection, VLP Biotech), AdTG-17909, AdTG-17910 AdTG-18202,ChronVac-B, TG-1050, and Lm HBV.

HBV DNA Polymerase Inhibitors

Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®),emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®),tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovirdipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethylester, CMX-157, besifovir, entecavir (BARACLUDE®), entecavir maleate,telbivudine (TYZEKA®), pradefovir, clevudine, ribavirin, lamivudine(EPIVIR-HBV®), phosphazide, famciclovir, fusolin, metacavir, SNC-019754,FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate,tenofovir disoproxil orotate, and HS-10234.

Immunomodulators

Examples of immunomodulators include rintatolimod, imidol hydrochloride,ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin,hydroxyurea, mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, INO-9112, polymerpolyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, RO-7011785,RO-6871765, and IR-103.

Toll-Like Receptor (TLR) Modulators

TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Examples of TLR3modulators include rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim,RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

Examples of TLR7 modulators include GS-9620, GSK-2245035, imiquimod,resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051,SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and thecompounds disclosed in US20100143301 (Gilead Sciences), US20110098248(Gilead Sciences), and US20090047249 (Gilead Sciences).

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051,3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and the compoundsdisclosed in US20140045849 (Janssen), US20140073642 (Janssen),WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189(Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen),US20080234251 (Array Biopharma), US20080306050 (Array Biopharma),US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma),US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), andUS20130251673 (Novira Therapeutics).

Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055,IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054,DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), litenimod, andCYT-003-QbG10.

Interferon Alpha Receptor Ligands

Examples of interferon alpha receptor ligands include interferonalpha-2b (INTRON A®), pegylated interferon alpha-2a (PEGASYS®),PEGylated interferon alpha-1b, interferon alpha 1b (HAPGEN®), Veldona,Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG-rhlFNalpha-2a),P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co(recombinant super compound Interferon), Ypeginterferon alfa-2b(YPEG-rhlFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-INTRON®),Bioferon, Novaferon, Inmutag (Inferon), MULTIFERON®, interferon alfa-n1(HUMOFERON®), interferon beta-1a (AVONEX®), Shaferon, interferon alfa-2b(Axxo), Alfaferone, interferon alfa-2b (BioGeneric Pharma),interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B,Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), interferon alfa 2a, Optipeg A, Realfa 2B, Reliferon,interferon alfa-2b (Amega), interferon alfa-2b (Virchow),ropeginterferon alfa-2b, rHSA-IFN alpha-2a (recombinant human serumalbumin intereferon alpha 2a fusion protein), rHSA-IFN alpha 2b,recombinant human interferon alpha-(1b, 2a, 2b), peginterferon alfa-2b(Amega), peginterferon alfa-2a, Reaferon-EC, Proquiferon, Uniferon,Urifron, interferon alfa-2b (Changchun Institute of BiologicalProducts), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b, and Interapo(Interapa).

Hyaluronidase Inhibitors

Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B Surface Antigen (HBsAg) Inhibitors

Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15,PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165,REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, andREP-9AC′.

Examples of HBsAg secretion inhibitors include BM601.

Cytotoxic T-Lymphocyte-Associated Protein 4 (Ipi4) Inhibitors

Examples of Cytotoxic T-lymphocyte-associated protein 4 (ipi4)inhibitors include AGEN-2041, AGEN-1884, ipilumimab, belatacept,PSI-001, PRS-010, Probody mAbs, tremelimumab, and JHL-1155.

Cyclophilin Inhibitors

Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030,SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosedin U.S. Pat. No. 8,513,184 (Gilead Sciences), US20140030221 (GileadSciences), US20130344030 (Gilead Sciences), and US20130344029 (GileadSciences).

HBV Viral Entry Inhibitors

Examples of HBV viral entry inhibitors include Myrcludex B.

Antisense Oligonucleotide Targeting Viral mRNA

Examples of antisense oligonucleotide targeting viral mRNA includeISIS-HBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404.

Short Interfering RNAs (siRNA) and ddRNAi.

Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008,HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

Endonuclease Modulators

Examples of endonuclease modulators include PGN-514.

Ribonucelotide Reductase Inhibitors

Examples of inhibitors of ribonucleotide reductase include Trimidox.

HBVE Antigen Inhibitors

Examples of HBV E antigen inhibitors include wogonin.

Covalently Closed Circular DNA (cccDNA) Inhibitors

Examples of cccDNA inhibitors include BSBI-25, and CHR-101.

Farnesoid X Receptor Agonist

Example of farnesoid x receptor agonist such as EYP-001.

HBV Antibodies

Examples of HBV antibodies targeting the surface antigens of thehepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV HepabulinSN, and fully human monoclonal antibody therapy (hepatitis B virusinfection, Humabs BioMed).

Examples of HBV antibodies, including monoclonal antibodies andpolyclonal antibodies, include Zutectra, Shang Sheng Gan Di, Uman Big(Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B,igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4,HBV infection, Shanghai RAAS Blood Products), and Fovepta (BT-088).

Fully human monoclonal antibodies such as HBC-34.

CCR2 Chemokine Antagonists

Examples of CCR2 chemokine antagonists include propagermanium.

Thymosin Agonists

Examples of thymosin agonists include Thymalfasin, recombinant thymosinalpha 1 (GeneScience)

Cytokines

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2(IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus),IL-15, IL-21, IL-24, and celmoleukin.

Nucleoprotein Modulators

Nucleoprotein modulators may be either HBV core or capsid proteininhibitors. Examples of nucleoprotein modulators include AT-130, GLS4,NVR-1221, NVR-3778, BAY 41-4109, morphothiadine mesilate, JNJ-379, andDVR-23. Capsid assembly inhibitors such as AB-423.

Examples of capsid inhibitors include the compounds disclosed inUS20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), US20140343032 (Roche), WO2014037480 (Roche),US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen),WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen),WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen),WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira),US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira),US20150197533 (Novira), US20150274652 (Novira), US20150259324, (Novira),US20150132258 (Novira), U.S. Pat. No. 9,181,288 (Novira), WO2014184350(Janssen), WO2013144129 (Roche).

Retinoic Acid-Inducible Gene 1 Stimulators

Examples of stimulators of retinoic acid-inducible gene 1 includeSB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198,and ORI-7170, RGT-100.

NOD2 Stimulators

Examples of stimulators of NOD2 include SB-9200.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186,AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib,rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib,IPI-549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584,copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093,pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414,SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.

Indoleamine-2, 3-dioxygenase (IDO) Pathway Inhibitors

Examples of IDO inhibitors include epacadostat (INCB24360), resminostat(4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028,GBV-1012, NKTR-218, and the compounds disclosed in US20100015178(Incyte), US2016137652 (Flexus Biosciences, Inc.), WO2014073738 (FlexusBiosciences, Inc.), and WO2015188085 (Flexus Biosciences, Inc.).

PD-1 Inhibitors

Examples of PD-1 inhibitors include nivolumab, pembrolizumab,pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226,STI-1110, and mDX-400.

PD-L1 Inhibitors

Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224,MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C,TSR-042, ALN-PDL, STI-A1014, CX-072, and BMS-936559.

Recombinant Thymosin Alpha-1

Examples of recombinant thymosin alpha-1 include NL-004 and PEGylatedthymosin alpha-1.

Bruton's Tyrosine Kinase (BTK) Inhibitors

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196),ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062,ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058,RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536,M-2951, TAK-020, AC-0025, and the compounds disclosed in US20140330015(Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical), andUS20130217880 (Ono Pharmaceutical).

KDM Inhibitors

Examples of KDM5 inhibitors include the compounds disclosed inWO2016057924 (Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096(Epitherapeutics), US20140194469 (Quanticel), US20140171432,US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel).

Examples of KDM1 inhibitors include the compounds disclosed in U.S. Pat.No. 9,186,337B2 (Oryzon Genomics), and GSK-2879552, RG-6016, ORY-2001.

HBV Replication Inhibitors

Examples of hepatitis B virus replication inhibitors includeisothiafludine, IQP-HBV, RM-5038, and Xingantie.

Arginase Inhibitors

Examples of Arginase inhibitors include CB-1158, C-201, and resminostat.

HBV Combination Therapy

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, or four additional therapeutic agent selected from the groupconsisting of adefovir (HEPSERA®), tenofovir disoproxil fumarate(VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil,tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate,entecavir (BARACLUDE®), telbivudine (TYZEKA®), or lamivudine(EPIVIR-HBV®). In a particular embodiment, a compound disclosed herein,or a pharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®). In one embodiment,pharmaceutical compositions comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, four, one or two, or one to three, or oneto four) additional therapeutic agents and a pharmaceutically acceptablecarrier, diluent, or excipient are provided.

HBV DNA Polymerase Inhibitor Combination Therapy

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor. In another specific embodiment, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with an HBV DNA polymerase inhibitor and at least oneadditional therapeutic agent selected from the group consisting of:immunomodulators, TLR modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, compounds targeting HBcAg, cyclophilininhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors,antisense oligonucleotide targeting viral mRNA, siRNA, miRNA genetherapy agents, endonuclease modulators, inhibitors of ribonucleotidereductase, hepatitis B virus E antigen inhibitors, recombinant SRAproteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors,sshRNAs, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies), CCR2chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators (HBV core or capsid protein modulators), stimulators ofretinoic acid-inducible gene 1, stimulators of RIG-I like receptors,stimulators of NOD2, stimulators of NOD1, Arginase inhibitors, STINGagonists, PI3K inhibitors, lymphotoxin beta receptor activators, naturalkiller cell receptor 2B4 inhibitors, Lymphocyte-activation gene 3inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein4 (ipi4) inhibitors, CD137 inhibitors, Killer cell lectin-like receptorsubfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyteattenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1inhibitors, PEG-Interferon Lambda, recombinant thymosin alpha-1, BTKinhibitors, modulators of TIGIT, modulators of CD47, modulators ofSIRPalpha, modulators of ICOS, modulators of CD27, modulators of CD70,modulators of OX40, epigenetic modifiers, modulators of NKG2D,modulators of Tim-4, modulators of B7-H4, modulators of B7-H3,modulators of NKG2A, modulators of GITR, modulators of CD160, modulatorsof HEVEM, modulators of CD161, modulators of Ax1, modulators of Mer,modulators of Tyro, gene modifiers or editors such as CRISPR (includingCRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs),IAPs inhibitors, SMAC mimetics, KDM5 inhibitors, IDO inhibitors, andhepatitis B virus replication inhibitors.

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor, one or two additional therapeutic agents selectedfrom the group consisting of immunomodulators, TLR modulators, HBsAginhibitors, HBsAg secretion or assembly inhibitors, HBV therapeuticvaccines, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies),cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1,stimulators of RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors,Arginase inhibitors, PI3K inhibitors, IDO inhibitors, and stimulators ofNOD2, and one or two additional therapeutic agents selected from thegroup consisting of HBV viral entry inhibitors, NTCP inhibitors, HBxinhibitors, cccDNA inhibitors, HBV antibodies targeting the surfaceantigens of the hepatitis B virus, siRNA, miRNA gene therapy agents,sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV core orcapsid protein modulators).

In another specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HBV DNApolymerase inhibitor and at least a second additional therapeutic agentselected from the group consisting of: HBV viral entry inhibitors, NTCPinhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targetingthe surface antigens of the hepatitis B virus, siRNA, miRNA gene therapyagents, sshRNAs, KDM5 inhibitors, and nucleoprotein modulators (HBV coreor capsid protein inhibitors).

HBV Drug Combination Therapy

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®), and at least asecond additional therapeutic agent selected from the group consistingof immunomodulators, TLR modulators, interferon alpha receptor ligands,hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAgsecretion or assembly inhibitors, compounds targeting HBcAg, cyclophilininhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors,antisense oligonucleotide targeting viral mRNA, siRNA, miRNA genetherapy agents, endonuclease modulators, inhibitors of ribonucleotidereductase, hepatitis B virus E antigen inhibitors, recombinant SRAproteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors,sshRNAs, HBV antibodies including HBV antibodies targeting the surfaceantigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, DUOBODIES®,BITES®, XmAbs®, TandAbs®, Fab derivatives, and TCR-like antibodies),CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoproteinmodulators (HBV core or capsid protein modulators), stimulators ofretinoic acid-inducible gene 1, stimulators of RIG-I like receptors,stimulators of NOD2, stimulators of NOD1, IDO inhibitors, recombinantthymosin alpha-1, Arginase inhibitors, STING agonists, PI3K inhibitors,lymphotoxin beta receptor activators, natural killer cell receptor 2B4inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors,ipi4 inhibitors, CD137 inhibitors, killer cell lectin-like receptorsubfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyteattenuator inhibitors, epigenetic modifiers, CD305 inhibitors, PD-1inhibitors, PD-L1 inhibitors, PEG-Interferon Lambd, BTK inhibitors,modulators of TIGIT, modulators of CD47, modulators of SIRPalpha,modulators of ICOS, modulators of CD27, modulators of CD70, modulatorsof OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4,modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulatorsof CD160, modulators of HEVEM, modulators of CD161, modulators of Ax1,modulators of Mer, modulators of Tyro, gene modifiers or editors such asCRISPR (including CRISPR Cas9), zinc finger nucleases or syntheticnucleases (TALENs), IAPs inhibitors, SMAC mimetics, KDM5 inhibitors, andhepatitis B virus replication inhibitors.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®) or lamivudine (EPIVIR-HBV®) and at least a secondadditional therapeutic agent selected from the group consisting ofpeginterferon alfa-2b (PEG-INTRON®), MULTIFERON®, interferon alpha 1b(HAPGEN®), interferon alpha-2b (INTRON A®), pegylated interferonalpha-2a (PEGASYS®), interferon alfa-n1 (HUMOFERON®), ribavirin,interferon beta-1a (AVONEX®), Bioferon, Ingaron, Inmutag (Inferon),Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b(AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron,interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B,BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B,interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b,Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b(Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b(Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega),Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b(Changchun Institute of Biological Products), Anterferon, Shanferon,MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2(Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai,INTEFEN, SINOGEN, Fukangtai, Alloferon, and celmoleukin.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:adefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®), and at least asecond additional therapeutic agent selected from the group consistingof HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNAinhibitors, HBV antibodies targeting the surface antigens of thehepatitis B virus, siRNA, miRNA gene therapy agents, sshRNAs, KDM5inhibitors, and nucleoprotein modulators (HBV core or capsid proteinmodulators).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); one, two, or threeadditional therapeutic agents selected from the group consisting ofimmunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion orassembly inhibitors, HBV therapeutic vaccines, HBV antibodies includingHBV antibodies targeting the surface antigens of the hepatitis B virusand bispecific antibodies and “antibody-like” therapeutic proteins (suchas DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2; and one or two additionaltherapeutic agents selected from the group consisting of HBV viral entryinhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBVantibodies targeting the surface antigens of the hepatitis B virus,siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, andnucleoprotein modulators (HBV core or capsid protein modulators).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); one or twoadditional therapeutic agents selected from the group consisting ofimmunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion orassembly inhibitors, HBV therapeutic vaccines, HBV antibodies includingHBV antibodies targeting the surface antigens of the hepatitis B virusand bispecific antibodies and “antibody-like” therapeutic proteins (suchas DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, orTCR-like antibodies), cyclophilin inhibitors, stimulators of retinoicacid-inducible gene 1, stimulators of RIG-I like receptors, PD-1inhibitors, PD-L1 inhibitors, Arginase inhibitors, PI3K inhibitors, IDOinhibitors, and stimulators of NOD2; and one or two additionaltherapeutic agents selected from the group consisting of HBV viral entryinhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBVantibodies targeting the surface antigens of the hepatitis B virus,siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors, andnucleoprotein modulators (HBV core or capsid protein modulators).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofadefovir (HEPSERA®), tenofovir disoproxil fumarate (VIREAD®), tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, entecavir (BARACLUDE®),telbivudine (TYZEKA®), or lamivudine (EPIVIR-HBV®); and one, two, three,or four additional therapeutic agents selected from the group consistingof immunomodulators, TLR7 modulators, TLR8 modulators, HBsAg inhibitors,HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBVantibodies including HBV antibodies targeting the surface antigens ofthe hepatitis B virus and bispecific antibodies and “antibody-like”therapeutic proteins (such as DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, or TCR-like antibodies), cyclophilininhibitors, stimulators of retinoic acid-inducible gene 1, stimulatorsof RIG-I like receptors, PD-1 inhibitors, PD-L1 inhibitors, Arginaseinhibitors, PI3K inhibitors, IDO inhibitors, stimulators of NOD2 HBVviral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNAinhibitors, siRNA, miRNA gene therapy agents, sshRNAs, KDM5 inhibitors,and nucleoprotein modulators (HBV core or capsid protein modulators).

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with compoundssuch as those disclosed in U.S. Publication No. 2010/0143301 (GileadSciences), U.S. Publication No. 2011/0098248 (Gilead Sciences), U.S.Publication No. 2009/0047249 (Gilead Sciences), U.S. Pat. No. 8,722,054(Gilead Sciences), U.S. Publication No. 2014/0045849 (Janssen), U.S.Publication No. 2014/0073642 (Janssen), WO2014/056953 (Janssen),WO2014/076221 (Janssen), WO2014/128189 (Janssen), U.S. Publication No.2014/0350031 (Janssen), WO2014/023813 (Janssen), U.S. Publication No.2008/0234251 (Array Biopharma), U.S. Publication No. 2008/0306050 (ArrayBiopharma), U.S. Publication No. 2010/0029585 (Ventirx Pharma), U.S.Publication No. 2011/0092485 (Ventirx Pharma), US2011/0118235 (VentirxPharma), U.S. Publication No. 2012/0082658 (Ventirx Pharma), U.S.Publication No. 2012/0219615 (Ventirx Pharma), U.S. Publication No.2014/0066432 (Ventirx Pharma), U.S. Publication No. 2014/0088085(Ventirx Pharma), U.S. Publication No. 2014/0275167 (NoviraTherapeutics), U.S. Publication No. 2013/0251673 (Novira Therapeutics),U.S. Pat. No. 8,513,184 (Gilead Sciences), U.S. Publication No.2014/0030221 (Gilead Sciences), U.S. Publication No. 2013/0344030(Gilead Sciences), U.S. Publication No. 2013/0344029 (Gilead Sciences),US20140275167 (Novira Therapeutics), US20130251673 (NoviraTherapeutics), U.S. Publication No. 2014/0343032 (Roche), WO2014037480(Roche), U.S. Publication No. 2013/0267517 (Roche), WO2014131847(Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167(Janssen), WO2015/059212 (Janssen), WO2015118057 (Janssen), WO2015011281(Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888(Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337(Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652(Novira), US20150259324, (Novira), US20150132258 (Novira), U.S. Pat. No.9,181,288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche),US20100015178 (Incyte), US2016137652 (Flexus Biosciences, Inc.),WO2014073738 (Flexus Biosciences, Inc.), WO2015188085 (FlexusBiosciences, Inc.), U.S. Publication No. 2014/0330015 (OnoPharmaceutical), U.S. Publication No. 2013/0079327 (Ono Pharmaceutical),U.S. Publication No. 2013/0217880 (Ono pharmaceutical), WO2016057924(Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096(Epitherapeutics), US20140194469 (Quanticel), US20140171432,US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel), U.S. Pat. No. 9,186,337B2 (OryzonGenomics), and other drugs for treating HBV, and combinations thereof.

In certain embodiments, a compound as disclosed herein (e.g., anycompound of Formula I) may be combined with one or more (e.g., one, two,three, four, one or two, one to three, or one to four) additionaltherapeutic agents in any dosage amount of the compound of Formula I(e.g., from 10 mg to 1000 mg of compound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofoviralafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofoviralafenamide. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 10 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide. A compound as disclosed herein(e.g., a compound of Formula I) may be combined with the agents providedherein in any dosage amount of the compound (e.g., from 50 mg to 500 mgof compound) the same as if each combination of dosages werespecifically and individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 100-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300;150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400;350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 300 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 250 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 150 mg tenofovir disoproxilfumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. Acompound as disclosed herein (e.g., a compound of Formula I) may becombined with the agents provided herein in any dosage amount of thecompound (e.g., from 50 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed.

In one embodiment, kits comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, four, one or two, or one to three, or oneto four) additional therapeutic agents are provided.

VII. COMBINATION THERAPY FOR HCV

In certain embodiments, a method for treating or preventing an HCVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound of the present disclosure, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents. In oneembodiment, a method for treating an HCV infection in a human having orat risk of having the infection is provided, comprising administering tothe human a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or more(e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating an HCV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents which are suitable for treating an HCVinfection.

In the above embodiments, the additional therapeutic agent may be ananti-HCV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of interferons,ribavirin or its analogs, HCV NS3 protease inhibitors, HCV NS4 proteaseinhibitors, HCV NS3/NS4 protease inhibitors, alpha-glucosidase 1inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors ofHCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase,HCV NS5A inhibitors, TLR7 agonists, cyclophilin inhibitors, HCV IRESinhibitors, and pharmacokinetic enhancers, compounds such as thosedisclosed in US2010/0310512, US2013/0102525, and WO2013/185093, orcombinations thereof.

In certain embodiments a compound of the present disclosure (e.g., acompound of Formula (I)) is formulated as a tablet, which may optionallycontain one or more other compounds useful for treating HCV. In certainembodiments, the tablet can contain another active ingredient fortreating HCV, such as interferons, ribavirin or its analogs, HCV NS3protease inhibitors, HCV NS4 protease inhibitors, HCV NS3/NS4 proteaseinhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants,nucleoside or nucleotide inhibitors of HCV NS5B polymerase,non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors,TLR7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, andpharmacokinetic enhancers, or combinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

-   (1) Interferons selected from the group consisting of pegylated    rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a (Pegasys),    rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon    alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin),    interferon alfacon-1 (Infergen), interferon alpha-n1 (Wellferon),    interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234),    interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b    (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021, glycosylated    interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon    lambda (PEGylated IL-29), or belerofon, IFN alpha-2b XL, rIFN-alpha    2a, consensus IFN alpha, infergen, rebif, pegylated IFN-beta, oral    interferon alpha, feron, reaferon, intermax alpha, r-IFN-beta, and    infergen+actimmuneribavirin and ribavirin analogs, e.g., rebetol,    copegus, VX-497, and viramidine (taribavirin);-   (2) Ribavirin and its analogs selected from the group consisting of    ribavirin (Rebetol, Copegus), and taribavirin (Viramidine);-   (3) NS5A inhibitors selected from the group consisting of Compound    A.1 (described below), Compound A.2 (described below), Compound A.3    (described below), ABT-267, Compound A.4 (described below),    JNJ-47910382, daclatasvir (BMS-790052), ABT-267, Samatasvir,    MK-8742, MK-8404, EDP-239, IDX-719, PPI-668, GSK-2336805, ACH-3102,    A-831, A-689, AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052;-   (4) NS5B polymerase inhibitors selected from the group consisting of    sofosbuvir (GS-7977), Compound A.5 (described below), Compound A.6    (described below), ABT-333, Compound A.7 (described below), ABT-072,    Compound A.8 (described below), tegobuvir (GS-9190), GS-9669,    TMC647055, ABT-333, ABT-072, setrobuvir (ANA-598), IDX-21437,    filibuvir (PF-868554), VX-222, IDX-375, IDX-184, IDX-102, BI-207127,    valopicitabine (NM-283), PSI-6130 (R1656), PSI-7851, BCX-4678,    nesbuvir (HCV-796), BILB 1941, MK-0608, NM-107, R7128, VCH-759,    GSK625433, XTL-2125, VCH-916, JTK-652, MK-3281, VBY-708, A848837,    GL59728, A-63890, A-48773, A-48547, BC-2329, BMS-791325, BILB-1941,    AL-335, AL-516 and ACH-3422;-   (5) Protease (NS3, NS3-NS4) inhibitors selected from the group    consisting of Compound A.9, Compound A.10, Compound A.11, ABT-450,    Compound A.12 (described below), simeprevir (TMC-435), boceprevir    (SCH-503034), narlaprevir (SCH-900518), vaniprevir (MK-7009),    MK-5172, danoprevir (ITMN-191), sovaprevir (ACH-1625), neceprevir    (ACH-2684), Telaprevir (VX-950), VX-813, VX-500, faldaprevir    (BI-201335), asunaprevir (BMS-650032), BMS-605339, VBY-376,    PHX-1766, YH5531, BILN-2065, and BILN-2061;-   (6) Alpha-glucosidase 1 inhibitors selected from the group    consisting of celgosivir (MX-3253), Miglitol, and UT-231B;-   (7) Hepatoprotectants selected from the group consisting of    emericasan (IDN-6556), ME-3738, GS-9450 (LB-84451), silibilin, and    MitoQ;-   (8) TLR7 agonists selected from the group consisting of imiquimod,    852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), and SM-360320;-   (9) Cyclophillin inhibitors selected from the group consisting of    DEBIO-025, SCY-635, and NIM811;-   (10) HCV IRES inhibitors selected from the group consisting of    MCI-067;-   (11) Pharmacokinetic enhancers selected from the group consisting of    BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, and    roxythromycin; and-   (12) Other anti-HCV agents selected from the group consisting of    thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401    (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101),    GS-9525, KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111,    ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C,    EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106    (ONO-4538), Oglufanide, VX-497 (merimepodib) NIM811, benzimidazole    derivatives, benzo-1,2,4-thiadiazine derivatives, and phenylalanine    derivatives;

Compound A.1 is an inhibitor of the HCV NS5A protein and is representedby the following chemical structure:

(see, e.g., U.S. Application Publication No. 20100310512 A1).

Compound A.2 is an NS5A inhibitor and is represented by the followingchemical structure:

Compound A.3 is an NS5A inhibitor and is represented by the followingchemical structure:

Compound A.4 is an NS5A inhibitor and is represented by the followingchemical structure:

(see U.S. Application Publication No. 2013/0102525 and referencestherein.)

Compound A.5 is an NS5B Thumb II polymerase inhibitor and is representedby the following chemical structure:

Compound A.6 is a nucleotide inhibitor prodrug designed to inhibitreplication of viral RNA by the HCV NS5B polymerase, and is representedby the following chemical structure:

Compound A.7 is an HCV polymerase inhibitor and is represented by thefollowing structure:

(see U.S. Application Publication No. 2013/0102525 and referencestherein).

Compound A.8 is an HCV polymerase inhibitor and is represented by thefollowing structure:

(see U.S. Application Publication No. 2013/0102525 and referencestherein).

Compound A.9 is an HCV protease inhibitor and is represented by thefollowing chemical structure:

Compound A.10 is an HCV protease inhibitor and is represented by thefollowing chemical structure:

Compound A.11 is an HCV protease inhibitor and is represented by thefollowing chemical structure:

Compound A.12 is an HCV protease inhibitor and is represented by thefollowing chemical structure:

(see U.S. Application Publication No. 2013/0102525 and referencestherein).

In one embodiment, the additional therapeutic agent used in combinationwith the pharmaceutical compositions as described herein is a HCV NS3protease inhibitor. Non-limiting examples include the following:

In another embodiment, the additional therapeutic agent used incombination with the pharmaceutical compositions as described herein isa cyclophillin inhibitor, including for example, a cyclophilin inhibitordisclosed in WO2013/185093. Non-limiting examples in addition to thoselisted above include the following:

and stereoisomers and mixtures of stereoisomers thereof.

In a specific embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a HCV NS5Bpolymerase inhibitor. In a specific embodiment, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with a HCV NS5B polymerase inhibitor and a HCV NS5A inhibitor.In another specific embodiment, a compound of the present disclosure, ora pharmaceutically acceptable salt thereof, is combined with a HCV NS5Bpolymerase inhibitor, a HCV NS3 protease inhibitor and a HCV NS5Ainhibitor. In another specific embodiment, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith a HCV NS5B polymerase inhibitor, a HCV NS4 protease inhibitor and aHCV NS5A inhibitor. In another specific embodiment, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with a HCV NS5B polymerase inhibitor, a HCV NS3/NS4 proteaseinhibitor and a HCV NS5A inhibitor. In another specific embodiment, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with a HCV NS3 protease inhibitor and a HCVNS5A inhibitor. In another specific embodiment, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with a HCV NS4 protease inhibitor and a HCV NS5A inhibitor. Inanother specific embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a HCV NS3/NS4protease inhibitor and a HCV NS5A inhibitor. In another specificembodiment, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with a HCV NS3 protease inhibitor,a pharmacokinetic enhancer and a HCV NS5A inhibitor. In another specificembodiment, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with a HCV NS4 protease inhibitor,a pharmacokinetic enhancer and a HCV NS5A inhibitor. In another specificembodiment, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with a HCV NS3/NS4 proteaseinhibitor, a pharmacokinetic enhancer and a HCV NS5A inhibitor.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected fromsimeprevir, MK-8742, MK-8408, MK-5172, ABT-450, ABT-267, ABT-333,sofosbuvir, sofosbuvir+ledipasvir, sofosbuvir+GS-5816,sofosbuvir+GS-9857+ledipasvir, ABT-450+ABT-267+ritonavir,ABT-450+ABT-267+ribavirin+ritonavir,ABT-450+ABT-267+ribavirin+ABT-333+ritonavir, ABT-530+ABT-493,MK-8742+MK-5172, MK-8408+MK-3682+MK-5172, MK-8742+MK-3682+MK-5172,daclatasvir, interferon, pegylated interferon, ribavirin, samatasvir,MK-3682, ACH-3422, AL-335, IDX-21437, IDX-21459, tegobuvir, setrobuvir,valopicitabine, boceprevir, narlaprevir, vaniprevir, danoprevir,sovaprevir, neceprevir, telaprevir, faldaprevir, asunaprevir,ledipasvir, GS-5816, GS-9857, ACH-3102, ACH-3422+ACH-3102,ACH-3422+sovaprevir+ACH-3102, asunaprevir, asunaprevir+daclatasvir,AL-516, and vedroprevir.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is co-administered withsimeprevir. In certain embodiments, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, isco-administered with MK-8742 or MK-8408. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with MK-5172. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with ABT-450, ABT-267, or ABT-333. Incertain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is co-administered withViekirat (a combination of ABT-450, ABT-267, and ritonavir). In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered with daclatasvir. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered with sofosbuvir. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered with Harvoni(sofosbuvir+ledipasvir). In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with sofosbuvir and GS-5816. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with sofosbuvir+GS-9857+ledipasvir. Incertain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is co-administered withABT-450+ABT-267+ribavirin+ritonavir. In certain embodiments, a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, is co-administered withABT-450+ABT-267+ribavirin+ABT-333+ritonavir. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with ABT-530+ABT-493. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered withMK-8408+MK-3682+MK-5172. In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with MK-8742+MK-5172. In certain embodiments, a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, is co-administered with MK-3682. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with ACH-3422. In certain embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with AL-335. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with ACH-3422+ACH-3102. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered withACH-3422+sovaprevir+ACH-3102. In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with GS-5816. In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with GS-9857. In certain embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, isco-administered with IDX-21459. In certain embodiments, a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,is co-administered with boceprevir. In certain embodiments, a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, is co-administered with ledipasvir. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is co-administered with AL-516.

In various methods, Compound A.1 is administered in an amount rangingfrom about 10 mg/day to about 200 mg/day. For example, the amount ofCompound A.1 can be about 30 mg/day, about 45 mg/day, about 60 mg/day,about 90 mg/day, about 120 mg/day, about 135 mg/day, about 150 mg/day,about 180 mg/day. In some methods, Compound A.1 is administered at about90 mg/day. In various methods, Compound A.2 is administered in an amountranging from about 50 mg/day to about 800 mg/day. For example, theamount of Compound A.2 can be about 100 mg/day, about 200 mg/day, orabout 400 mg/day. In some methods, the amount of Compound A.3 is about10 mg/day to about 200 mg/day. For example, the amount of Compound A.3can be about 25 mg/day, about 50 mg/day, about 75 mg/day, or about 100mg/day.

In various methods, sofosbuvir is administered in an amount ranging fromabout 10 mg/day to about 1000 mg/day. For example, the amount ofsofosbuvir can be about 100 mg/day, about 200 mg/day, about 300 mg/day,about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day,about 800 mg/day. In some methods, sofosbuvir is administered at about400 mg/day.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,and one or more additional therapeutic agents for treating HCV, for usein a method of treating or preventing HCV.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in a method of treating or preventing HCV, wherein the compoundor a pharmaceutically acceptable salt thereof is administeredsimultaneously, separately or sequentially with one or more additionaltherapeutic agents for treating HCV.

VIII. COMBINATION THERAPY FOR HIV

In certain embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound of the present disclosure, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents. In oneembodiment, a method for treating an HIV infection in a human having orat risk of having the infection is provided, comprising administering tothe human a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or more(e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt, thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents which are suitable for treating an HIVinfection. In certain embodiments, one or more additional therapeuticagents includes, for example, one, two, three, four, one or two, one tothree or one to four additional therapeutic agents.

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachmentinhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidaseinhibitors, HIV vaccines, HIV maturation inhibitors, latency reversingagents (e.g., histone deacetylase inhibitors, proteasome inhibitors,protein kinase C (PKC) activators, and BRD4 inhibitors), compounds thattarget the HIV capsid (“capsid inhibitors”; e.g., capsid polymerizationinhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7)inhibitors, HIV p24 capsid protein inhibitors), pharmacokineticenhancers, immune-based therapies (e.g., Pd-1 modulators, Pd-L1modulators, toll like receptors modulators, IL-15 agonists,), HIVantibodies, bispecific antibodies and “antibody-like” therapeuticproteins (e.g., DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fabderivatives) including those targeting HIV gp120 or gp41, combinationdrugs for HIV, HIV p17 matrix protein inhibitors, IL-13 antagonists,Peptidyl-prolyl cis-trans isomerase A modulators, Protein disulfideisomerase inhibitors, Complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors,Integrin antagonists, Nucleoprotein inhibitors, Splicing factormodulators, COMM domain containing protein 1 modulators, HIVRibonuclease H inhibitors, Retrocyclin modulators, CDK-9 inhibitors,Dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,Ubiquitin ligase inhibitors, Deoxycytidine kinase inhibitors, Cyclindependent kinase inhibitors Proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, PI3K inhibitors, compounds such as those disclosedin WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University ofPennsylvania), WO 2013/091096A1 (Boehringer Ingelheim), WO 2009/062285(Boehringer Ingelheim), US20140221380 (Japan Tobacco), US20140221378(Japan Tobacco), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064(Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497(Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728(Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498(Gilead Sciences) and WO 2013/006792 (Pharma Resources), and other drugsfor treating HIV, and combinations thereof. In some embodiments, theadditional therapeutic agent is further selected from Vif dimerizationantagonists and HIV gene therapy.

In certain embodiments, the additional therapeutic is selected from thegroup consisting of HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,pharmacokinetic enhancers, and combinations thereof.

In certain embodiments a compound of the present disclosure isformulated as a tablet, which may optionally contain one or more othercompounds useful for treating HIV. In certain embodiments, the tabletcan contain another active ingredient for treating HIV, such as HIVprotease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors ofreverse transcriptase, HIV nucleoside or nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site(or allosteric) integrase inhibitors, pharmacokinetic enhancers, andcombinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

-   (1) Combination drugs selected from the group consisting of ATRIPLA®    (efavirenz+tenofovir disoproxil fumarate+emtricitabine), COMPLERA®    (EVIPLERA®, rilpivirine+tenofovir disoproxil    fumarate+emtricitabine), STRIBILD®    (elvitegravir+cobicistat+tenofovir disoproxil    fumarate+emtricitabine), dolutegravir+abacavir sulfate+lamivudine,    TRIUMEQ® (dolutegravir+abacavir+lamivudine),    lamivudine+nevirapine+zidovudine, dolutegravir+rilpivirine,    atazanavir sulfate+cobicistat, darunavir+cobicistat,    efavirenz+lamivudine+tenofovir disoproxil fumarate, tenofovir    alafenamide hemifumarate+emtricitabine+cobicistat+elvitegravir,    Vacc-4x+romidepsin, darunavir+tenofovir alafenamide    hemifumarate+emtricitabine+cobicistat, APH-0812,    raltegravir+lamivudine, KALETRA® (ALUVIA®, lopinavir+ritonavir),    atazanavir sulfate+ritonavir, COMBIVIR® (zidovudine+lamivudine,    AZT+3TC), EPZICOM® (Livexa®, abacavir sulfate+lamivudine, ABC+3TC),    TRIZIVIR® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC),    TRUVADA® (tenofovir disoproxil fumarate+emtricitabine, TDF+FTC),    tenofovir+lamivudine and lamivudine+tenofovir disoproxil fumarate,    as well as combinations drugs selected from dolutegravir+rilpivirine    hydrochloride, atazanavir+cobicistat, tenofovir alafenamide    hemifumarate+emtricitabine, tenofovir alafenamide+emtricitabine,    tenofovir alafenamide hemifumarate+emtricitabine+rilpivirine,    tenofovir alafenamide+emtricitabine+rilpivirine,    doravirine+lamivudine+tenofovir disoproxil fumarate,    doravirine+lamivudine+tenofovir disoproxil;-   (2) HIV protease inhibitors selected from the group consisting of    amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium,    indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir,    nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir,    brecanavir, darunavir, DG-17, TMB-657 (PPL-100) and TMC-310911;-   (3) HIV non-nucleoside or non-nucleotide inhibitors of reverse    transcriptase selected from the group consisting of delavirdine,    delavirdine mesylate, nevirapine, etravirine, dapivirine,    doravirine, rilpivirine, efavirenz, KM-023, VM-1500, lentinan and    AIC-292;-   (4) HIV nucleoside or nucleotide inhibitors of reverse transcriptase    selected from the group consisting of VIDEX® and VIDEX® EC    (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine,    zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate,    amdoxovir, elvucitabine, alovudine, phosphazid, fozivudine tidoxil,    apricitabine, amdoxovir, KP-1461, fosalvudine tidoxil, tenofovir,    tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir    disoproxil hemifumarate, tenofovir alafenamide, tenofovir    alafenamide hemifumarate, tenofovir alafenamide fumarate, adefovir,    adefovir dipivoxil, and festinavir;-   (5) HIV integrase inhibitors selected from the group consisting of    curcumin, derivatives of curcumin, chicoric acid, derivatives of    chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of    3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of    aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives    of caffeic acid phenethyl ester, tyrphostin, derivatives of    tyrphostin, quercetin, derivatives of quercetin, raltegravir,    elvitegravir, dolutegravir and cabotegravir, as well as HIV    integrase inhibitors selected from JTK-351;-   (6) HIV non-catalytic site, or allosteric, integrase inhibitors    (NCINI) selected from the group consisting of CX-05168, CX-05045 and    CX-14442;-   (7) HIV gp41 inhibitors selected from the group consisting of    enfuvirtide, sifuvirtide and albuvirtide;-   (8) HIV entry inhibitors selected from the group consisting of    cenicriviroc;-   (9) HIV gp120 inhibitors selected from the group consisting of    Radha-108 (Receptol) and BMS-663068;-   (10) CCR5 inhibitors selected from the group consisting of    aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, Adaptavir    (RAP-101), TBR-220 (TAK-220), nifeviroc (TD-0232), TD-0680, and vMIP    (Haimipu);-   (11) CD4 attachment inhibitors selected from the group consisting of    ibalizumab;-   (12) CXCR4 inhibitors selected from the group consisting of    plerixafor, ALT-1188, vMIP and Haimipu;-   (13) Pharmacokinetic enhancers selected from the group consisting of    cobicistat and ritonavir;-   (14) Immune-based therapies selected from the group consisting of    dermaVir, interleukin-7, plaquenil (hydroxychloroquine), proleukin    (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon    alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea,    mycophenolate mofetil (MPA) and its ester derivative mycophenolate    mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, polymer    polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like    receptors modulators (TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7,    TLR8, TLR9, TLR10, TLR11, TLR12 and TLR13), rintatolimod and IR-103;-   (15) HIV vaccines selected from the group consisting of peptide    vaccines, recombinant subunit protein vaccines, live vector    vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion    vaccine), CD4-derived peptide vaccines, vaccine combinations, rgp120    (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), Remune,    ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409,    Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5    (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine,    AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51,    poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06),    AGS-004, gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag    vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2,    NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, Vichrepol, rAAV1-PG9DP,    GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4    (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01,    SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR,    ETV-01 and DNA-Ad5 gag/pol/nef/nev (HVTN505), as well as HIV    vaccines selected from monomeric gp120 HIV-1 subtype C vaccine    (Novartis), HIV-TriMix-mRNA, MVATG-17401, ETV-01, CDX-1401, and    rcAd26.MOS1.HIV-Env;-   (16) HIV antibodies, bispecific antibodies and “antibody-like”    therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®,    TandAbs®, Fab derivatives) including BMS-936559, TMB-360 and those    targeting HIV gp120 or gp41 selected from the group consisting of    bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10,    3-BNC-117, PGT145, PGT121, MDXO10 (ipilimumab), VRC01, A32, 7B2,    10E8 and VRC07, as well as HIV antibodies such as VRC-07-523;-   (17) latency reversing agents selected from the group consisting of    Histone deacetylase inhibitors such as Romidepsin, vorinostat,    panobinostat; Proteasome inhibitors such as Velcade; protein kinase    C (PKC) activators such as Indolactam, Prostratin, Ingenol B and    DAG-lactones, lonomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15,    JQ1, disulfram, and amphotericin B;-   (18) HIV nucleocapsid p7 (NCp7) inhibitors selected from the group    consisting of azodicarbonamide;-   (19) HIV maturation inhibitors selected from the group consisting of    BMS-955176 and GSK-2838232;-   (20) PI3K inhibitors selected from the group consisting of    idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib,    rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib,    duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584,    copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423,    panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093,    pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319,    RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib,    LY-3023414, SAR-260301 and CLR-1401;-   (21) the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO    2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO    2013/006738 (Gilead Sciences), US 2013/0165489 (University of    Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan    Tobacco), WO 2013/006792 (Pharma Resources), WO 2009/062285    (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO    2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead    Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Gilead    Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead    Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498    (Gilead Sciences); and-   (22) other drugs for treating HIV selected from the group consisting    of BanLec, MK-8507, AG-1105, TR-452, MK-8591, REP 9, CYT-107,    alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan,    Gamimune, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN,    VSSP, H1viral, IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43,    MK-1376, rHIV7-sh1-TAR-CCR5RZ, MazF gene therapy, BlockAide,    ABX-464, SCY-635, naltrexone and PA-1050040 (PA-040); and other    drugs for treating HIV selected from AAV-eCD4-Ig gene therapy,    TEV-90110, TEV-90112, TEV-90111, TEV-90113, deferiprone, and    HS-10234.

In certain embodiments, the additional therapeutic agent is a compounddisclosed in US 2014-0221356 (Gilead Sciences, Inc.) for example(2R,5S,13aR)—N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(2S,5R,13aS)—N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(1S,4R,12aR)—N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,and(1R,4S,12aR)—N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,US2015-0018298 (Gilead Sciences, Inc.) and US2015-0018359 (GileadSciences, Inc.),

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In certainembodiments, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In a specific embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase and an HIVnon-nucleoside inhibitor of reverse transcriptase. In another specificembodiment, a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, and an HIV proteaseinhibiting compound. In a further embodiment, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith an HIV nucleoside or nucleotide inhibitor of reverse transcriptase,an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIVprotease inhibiting compound. In an additional embodiment, a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,is combined with an HIV nucleoside or nucleotide inhibitor of reversetranscriptase, an HIV non-nucleoside inhibitor of reverse transcriptase,and a pharmacokinetic enhancer. In certain embodiments, a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,is combined with one or more additional therapeutic agents selected fromHIV nucleoside inhibitor of reverse transcriptase, an integraseinhibitor, and a pharmacokinetic enhancer. In another embodiment, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with two HIV nucleoside or nucleotideinhibitors of reverse transcriptase.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from Triumeq®(dolutegravir+abacavir+lamivudine), dolutegravir+abacavirsulfate+lamivudine, raltegravir, Truvada® (tenofovir disoproxilfumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom®(Livexa®, abacavir sulfate+lamivudine, ABC+3TC), Trizivir® (abacavirsulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovirdipivoxil, Stribild® (elvitegravir+cobicistat+tenofovir disoproxilfumarate+emtricitabine), rilpivirine, rilpivirine hydrochloride,Complera® (Eviplera®, rilpivirine+tenofovir disoproxilfumarate+emtricitabine), Cobicistat, Atripla® (efavirenz+tenofovirdisoproxil fumarate+emtricitabine), atazanavir, atazanavir sulfate,dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir),ritonavir, emtricitabine, atazanavir sulfate+ritonavir, darunavir,lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz,Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir,nelfinavir mesylate, interferon, didanosine, stavudine, indinavir,indinavir sulfate, tenofovir+lamivudine, zidovudine, nevirapine,saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir,amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol),H1viral, lamivudine+tenofovir disoproxil fumarate,efavirenz+lamivudine+tenofovir disoproxil fumarate, phosphazid,lamivudine+nevirapine+zidovudine, abacavir, abacavir sulfate, tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide and tenofovir alafenamide hemifumarate. In certainembodiments, the one, two, three, four or more additional therapeuticagents are further selected from raltegravir+lamivudine, atazanavirsulfate+cobicistat, atazanavir+cobicistat, darunavir+cobicistat,darunavir+cobicistat, atazanavir sulfate+cobicistat,atazanavir+cobicistat.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from Triumeq®(dolutegravir+abacavir+lamivudine), dolutegravir+abacavirsulfate+lamivudine, raltegravir, Truvada® (tenofovir disoproxilfumarate+emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom®(Livexa®, abacavir sulfate+lamivudine, ABC+3TC), Trizivir® (abacavirsulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovirdipivoxil, Stribild® (elvitegravir+cobicistat+tenofovir disoproxilfumarate+emtricitabine), rilpivirine, rilpivirine hydrochloride,Complera® (Eviplera®, rilpivirine+tenofovir disoproxilfumarate+emtricitabine), cobicistat, Atripla® (efavirenz+tenofovirdisoproxil fumarate+emtricitabine), atazanavir, atazanavir sulfate,dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir),ritonavir, emtricitabine, atazanavir sulfate+ritonavir, darunavir,lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz,Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir,nelfinavir mesylate, interferon, didanosine, stavudine, indinavir,indinavir sulfate, tenofovir+lamivudine, zidovudine, nevirapine,saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir,amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol),H1viral, lamivudine+tenofovir disoproxil fumarate,efavirenz+lamivudine+tenofovir disoproxil fumarate, phosphazid,lamivudine+nevirapine+zidovudine,(2R,5S,13aR)—N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(2S,5R,13aS)—N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(1S,4R,12aR)—N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,and (1R,4S,12aR)—N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamideabacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovirdisoproxil fumarate, tenofovir alafenamide and tenofovir alafenamidehemifumarate.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide or tenofoviralafenamide hemifumarate.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarateand a second additional therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, and tenofovir alafenamide hemifumarate and asecond additional therapeutic agent, wherein the second additionaltherapeutic agent is emtricitabine.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide and 200 mg emtricitabine. In certain embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30;15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. Incertain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with 10 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide and 200 mg emtricitabine. In certain embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with 25 mg tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mgemtricitabine. A compound of the present disclosure (e.g., a compound offormula (I)) may be combined with the agents provided herein in anydosage amount of the compound (e.g., from 1 mg to 500 mg of compound)the same as if each combination of dosages were specifically andindividually listed.

In certain embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil and 200 mg emtricitabine. In certain embodiments, acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with 200-250; 200-300; 200-350; 250-350;250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mgemtricitabine. In certain embodiments, a compound of the presentdisclosure, or a pharmaceutically acceptable salt thereof, is combinedwith 300 mg tenofovir disoproxil fumarate, tenofovir disoproxilhemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. Acompound of the present disclosure (e.g., a compound of formula (I)) maybe combined with the agents provided herein in any dosage amount of thecompound (e.g., from 50 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed. Acompound of the present disclosure (e.g., a compound of Formula (I)) maybe combined with the agents provided herein in any dosage amount of thecompound (e.g. from about 1 mg to about 150 mg of compound) the same asif each combination of dosages were specifically and individuallylisted.

In certain embodiments a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with(2R,5S,13aR)—N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(2S,5R,13aS)—N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,(1S,4R,12aR)—N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide,(2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,or(1R,4S,12aR)—N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1′,2′-d]pyrazine-9-carboxamide.

Also provided herein is a compound the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,and one or more additional therapeutic agents for treating HIV, for usein a method of treating or preventing HIV.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in a method of treating or preventing HIV, wherein the compoundor a pharmaceutically acceptable salt thereof is administeredsimultaneously, separately or sequentially with one or more additionaltherapeutic agents for treating HIV.

In certain embodiments, a method for treating hyperproliferativedisorders such as cancer in a human is provided, comprisingadministering to the human a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, in combination with a therapeutically effective amount ofone or more (e.g., one, two, three, one or two, or one to three)additional therapeutic agents. In one embodiment, a method for treatinghyperproliferative disorders such as cancer in a human is provided,comprising administering to the human a therapeutically effective amountof a compound of the present disclosure, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents.

IX. COMBINATION THERAPY FOR CANCER

In certain embodiments, the present disclosure provides a method fortreating hyperproliferative disorders such as cancer, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of the present disclosure, or a pharmaceuticallyacceptable salt, thereof, in combination with a therapeuticallyeffective amount of one or more additional therapeutic agents which aresuitable for treating hyperproliferative disorders such as cancer.

In the above embodiments, the additional therapeutic agent may be ananti-cancer agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting ofchemotherapeutic agents, immunotherapeutic agents, radiotherapeuticagents, anti-neoplastic agents, anti-hormonal agents, anti-angiogenicagents, anti-fibrotic agents, therapeutic antibodies, tyrosine kinaseinhibitors, JAK inhibitors, Hedgehog inhibitors, HDAC inhibitors,Discoidin domain receptor (DDR) inhibitors, MMP9 inhibitors, LOXLinhibitors, ASK1 inhibitors, PI3K inhibitors, BTK inhibitors, SYKinhibitors, mTOR inhibitors, AKT inhibitors, Mitogen or ExtracellularRegulated Kinase (MEK) inhibitors, blockers of Raf kinases (rafk), CDKinhibitors, JNK inhibitors, MAPK inhibitors, Raf inhibitors, ROCKinhibitors, Tie2 inhibitors, Myo-inositol signaling inhibitors,phospholipase C blockers, anti-CD19 antibodies, anti-CD20 antibodies,anti-MN-14 antibodies, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74antibodies, cancer vaccines based upon the genetic makeup of anindividual patient's tumor, IDH1 inhibitors, BRD4 inhibitors, TPL2inhibitors; A2B inhibitors; TBK1 inhibitors; IKK inhibitors; BCRinhibitors, agents inhibiting the RAS/RAF/ERK pathway, protein kinase C(PKC) modulators, modulators of growth factor receptors such asepidermal growth factor receptor (EGFr), platelet derived growth factorreceptor (PDGFr), erbB2, erbB4, ret, vascular endothelial growth factorreceptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermalgrowth factor homology domains (TIE-2), insulin growth factor-I (IGFI)receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet,fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, andTrkC), ephrin (eph) receptors, and the RET protooncogene, modulators oftyrosine kinases including cSrc, Lck, Fyn, Yes, cAbl, FAK (Focaladhesion kinase) and Bcr-Abl, modulators of PKB family kinases,modulators of TGF beta receptor kinases, inhibitors of Ras oncogeneincluding inhibitors of famesyltransferase, geranyl-geranyl transferase,and CAAX proteases, anti-sense oligonucleotides, ribozymes, Bcl-2 familyprotein inhibitors, proteasome inhibitors, Heat shock protein HSP90inhibitors, combination drugs and immunotherapy, and other drugs fortreating hyperproliferative disorders such as cancer, and combinationsthereof.

In certain embodiments a compound of the present disclosure isformulated as a tablet, which may optionally contain one or more othercompounds useful for treating cancer. In certain embodiments, the tabletcan contain another active ingredient for treating cancer, such aschemotherapeutic agents, immunotherapeutic agents, radiotherapeuticagents, anti-neoplastic agents, anti-fibrotic agents, anti-hormonalagents, anti-angiogenic agents, Tyrosine kinase inhibitors, JAKinhibitors, Hedgehog inhibitors, HDAC inhibitors, Discoidin domainreceptor (DDR) inhibitors, MMP9 inhibitors, LOXL inhibitors, ASK1inhibitors, PI3K inhibitors, BTK inhibitors, SYK inhibitors, mTORinhibitors, AKT inhibitors, Mitogen or Extracellular Regulated Kinase(MEK) inhibitors, blockers of Raf kinases (rafk), CDK inhibitors, JNKinhibitors, MAPK inhibitors, Raf inhibitors, ROCK inhibitors, Tie2inhibitors, Myo-inositol signaling inhibitors, phospholipase C blockers,IDH1 inhibitors, BRD4 inhibitors, TPL2 inhibitors; A2B inhibitors; TBK1inhibitors; IKK inhibitors; BCR inhibitors, agents inhibiting theRAS/RAF/ERK pathway, protein kinase C (PKC) modulators, modulators ofgrowth factor receptors such as epidermal growth factor receptor (EGFr),platelet derived growth factor receptor (PDGFr), erbB2, erbB4, ret,vascular endothelial growth factor receptor (VEGFr), tyrosine kinasewith immunoglobulin-like and epidermal growth factor homology domains(TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colonystimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor(FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph)receptors, and the RET protooncogene, modulators of tyrosine kinasesincluding cSrc, Lck, Fyn, Yes, cAbl, FAK (Focal adhesion kinase) andBcr-Abl, modulators of PKB family kinases, modulators of TGF betareceptor kinases, inhibitors of Ras oncogene including inhibitors offamesyltransferase, geranyl-geranyl transferase, and CAAX proteases,anti-sense oligonucleotides, ribozymes, Bcl-2 family protein inhibitors,proteasome inhibitors, Heat shock protein HSP90 inhibitors, combinationdrugs and immunotherapy, and other drugs for treating hyperproliferativedisorders such as cancer, and combinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

-   (1) Chemotherapeutic agents selected from the group consisting of:    anti-metabolites/anti-cancer agents, such as pyrimidine analogs    (floxuridine, capecitabine, and cytarabine); purine analogs, folate    antagonists and related inhibitors, antiproliferative/antimitotic    agents including natural products such as vinca alkaloid    (vinblastine, vincristine) and microtubule such as taxane    (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and    navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA    damaging agents (actinomycin, amsacrine, busulfan, carboplatin,    chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin,    daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan,    merchlorehtamine, mitomycin, mitoxantrone, nitrosourea,    procarbazine, taxol, taxotere, teniposide, etoposide,    triethylenethiophosphoramide); antibiotics such as dactinomycin    (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin,    anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin)    and mitomycin; enzymes (L-asparaginase which systemically    metabolizes L-asparagine and deprives cells which do not have the    capacity to synthesize their own asparagine); antiplatelet agents;    antiproliferative/antimitotic alkylating agents such as nitrogen    mustards cyclophosphamide and analogs, melphalan, chlorambucil), and    (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and    analogs, streptozocin, trazenes-dacarbazinine (DTIC);    antiproliferative/antimitotic antimetabolites such as folic acid    analogs (methotrexate); platinum coordination complexes (cisplatin,    oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane,    aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen,    goserelin, bicalutamide, nilutamide) and aromatase inhibitors    (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin    salts and other inhibitors of thrombin); fibrinolytic agents (such    as tissue plasminogen activator, streptokinase and urokinase),    aspirin, dipyridamole, ticlopidine, clopidogrel; antimigratory    agents; antisecretory agents (breveldin); immunosuppressives    tacrolimus, sirolimus azathioprine, mycophenolate; compounds    (TNP-470, genistein) and growth factor inhibitors (vascular    endothelial growth factor inhibitors, fibroblast growth factor    inhibitors); angiotensin receptor blocker, nitric oxide donors;    anti-sense oligonucleotides; cell cycle inhibitors and    differentiation inducers (tretinoin); inhibitors, topoisomerase    inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin,    eniposide, epirubicin, idarubicin, irinotecan and mitoxantrone,    topotecan, irinotecan), corticosteroids (cortisone, dexamethasone,    hydrocortisone, methylpednisolone, prednisone, and prednisolone);    growth factor signal transduction kinase inhibitors; dysfunction    inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin,    Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin,    and caspase activators, chromatin, alkylating agents such as    thiotepa and cyclophosphamide (Cytoxan, Endoxan, Endoxana,    Cyclostin), alkyl sulfonates such as busulfan, improsulfan and    piposulfan; aziridines such as benzodopa, carboquone, meturedopa,    and uredopa; emylerumines and memylamelamines including alfretamine,    triemylenemelamine, triethylenephosphoramide,    triethylenethiophosphoramide and trimemylolomelamine; acetogenins    (especially bullatacin and bullatacinone); a camptothecin (including    synthetic analogue topotecan); bryostatin; callystatin; CC-1065    (including its adozelesin, carzelesin and bizelesin synthetic    analogues); cryptophycins (articularly cryptophycin 1 and    cryptophycin 8); dolastatin; duocarmycin (including the synthetic    analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a    sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,    chlomaphazine, cholophosphamide, estramustine, ifosfamide,    mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,    novembichin, phenesterine, prednimustine, trofosfamide, uracil    mustard; nitrosoureas such as carmustine, chlorozotocin,    foremustine, lomustine, nimustine, ranimustine; antibiotics such as    the enediyne antibiotics (e.g., calicheamicin, especially    calicheamicin gammall and calicheamicin phill, see, e.g., Agnew,    Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including    dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as    well as neocarzinostatin chromophore and related chromoprotein    enediyne antibiotic chromomophores), aclacinomysins, actinomycin,    authramycin, azaserine, bleomycins, cactinomycin, carabicin,    carminomycin, carzinophilin, chromomycins, dactinomycin,    daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin    (including morpholino-doxorubicin, cyanomorpholino-doxorubicin,    2-pyrrolino-doxorubicin, PEGylated liposomal doxorubicin and    deoxydoxorubicin), epirubicin, esorubicin, idarubicin,    marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,    nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,    quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,    ubenimex, zinostatin, zorubicin; anti-metabolites such as    methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as    demopterin, methotrexate, pteropterin, trimetrexate; purine analogs    such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;    pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine,    carmofur, dideoxyuridine, doxifluridine, enocitabine, floxuridine;    androgens such as calusterone, dromostanolone propionate,    epitiostanol, mepitiostane, testolactone; anti-adrenals such as    aminoglutethimide, mitotane, trilostane; folic acid replinisher such    as frolinic acid; aceglatone; aldophosphamide glycoside;    aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene;    edatraxate; defofamine; demecolcine; diaziquone; elformthine;    elliptinium acetate; an epothilone; etoglucid; gallium nitrate;    hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as    maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol;    nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone;    fluoropyrimidine; folinic acid; podophyllinic acid;    2-ethylhydrazide; procarbazine; PSK(r); razoxane; rhizoxin;    sizofiran; spirogermanium; tenuazonic acid; triaziquone;    2,2′,2″-tricUorotriemylamine; trichothecenes (especially T-2 toxin,    verracurin A, roridin A and anguidine); urethane; vindesine;    dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;    gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta;    taxoids, paclitaxel (Taxol) and docetaxel (Taxotere); chlorambucil;    gemcitabine (Gemzar); 6-thioguanine; mercaptopurine; methotrexate;    platinum analogs such as cisplatin and carboplatin; platinum;    ifosfamide; mitroxantrone; vancristine; vinorelbine (Navelbine);    novantrone; teniposide; edatrexate; daunomycin; aminopterin;    xeoloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;    difluoromethylornithine (DMFO); retinoids such as retinoic acid;    capecitabine and FOLFIRI (fluorouracil, leucovorin, and irinotecan);-   (2) Anti-hormonal agents selected from the group consisting of:    anti-estrogens and selective estrogen receptor modulators (SERMs),    including, for example, tamoxifen (including Nolvadex), raloxifene,    droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018,    onapristone, and toremifene; inhibitors of the enzyme aromatase,    which regulates estrogen production in the adrenal glands, such as,    for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate,    exemestane, formestane, fadrozole, vorozole, letrozole and    anastrozole, and anti-androgens such as flutamide, nilutamide,    bicalutamide, leuprolide, and goserelin;-   (3) Anti-angiogenic agents selected from the group consisting of:    retinoid acid and derivatives thereof, 2-methoxyestradiol,    ANGIOSTATIN, ENDOSTATIN, suramin, squalamine, tissue inhibitors of    metalloproteinase-1, tissue inhibitors of metalloproteinase-2,    plasminogen activator inhibitor-1, plasminogen activator    inhibitor-2, cartilage-derived inhibitors, paclitaxel    (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine),    sulphated chitin derivatives (prepared from queen crab shells),    sulphated polysaccharide peptidoglycan complex (sp-pg),    staurosporine, modulators of matrix metabolism, including for    example, proline analogs ((1-azetidine-2-carboxylic acid (LACA),    cishydroxyproline, d,I-3,4-dehydroproline, thiaproline,    .alpha.-dipyridyl, beta-aminopropionitrile fumarate,    4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate,    mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3,    chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin;    fumagillin, gold sodium thiomalate, d-penicillamine (CDPT),    beta-1-anticollagenase-serum, alpba-2-antiplasmin, bisantrene,    lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid    disodium or “CCA”, thalidomide; angiostatic steroid,    cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94,    antibodies, preferably monoclonal antibodies against these    angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF    isoforms, VEGF-C, HGF/SF, Ang-1/Ang-2 and the compounds disclosed in    Ferrara N. and Alitalo, K. “Clinical application of angiogenic    growth factors and their inhibitors” (1999) Nature Medicine    5:1359-1364;-   (4) Anti-fibrotic agents selected from the group consisting of:    beta-aminoproprionitrile (BAPN), primary amines reacting with the    carbonyl group of the active site of the lysyl oxidases, and more    particularly those which produce, after binding with the carbonyl, a    product stabilized by resonance, such as the following primary    amines: emylenemamine, hydrazine, phenylhydrazine, and their    derivatives, semicarbazide, and urea derivatives, aminonitriles,    such as beta-aminopropionitrile (BAPN), or 2-nitroethylamine,    unsaturated or saturated haloamines, such as 2-bromo-ethylamine,    2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine,    p-halobenzylamines, selenohomocysteine lactone, copper chelating    agents, indirect inhibitors such as compounds blocking the aldehyde    derivatives originating from the oxidative deamination of the lysyl    and hydroxylysyl residues by the lysyl oxidases, such as the    thiolamines, in particular D-penicillamine, or its analogues such as    2-amino-5-mercapto-5-methylhexanoic acid,    D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,    p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,    sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane    sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate,    sodium-4-mercaptobutanesulphinate trihydrate, the compounds    disclosed in U.S. Pat. Nos. 4,965,288, 4,997,854, 4,943,593,    5,021,456; 5,5059,714; 5,120,764; 5,182,297; 5,252,608 and U.S.    Patent Application No. 2004/0248871;-   (5) Therapeutic antibodies selected from the group consisting of:    abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab,    amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab,    bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab,    catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab,    conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab,    detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab,    ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab,    figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab,    girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab,    indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab,    labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab,    mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab,    moxetumomab, namatumab, naptumomab, necitumumab, nimotuzumab,    nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab,    oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab,    pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab,    radretumab, rilotumumab, rituximab, robatumumab, satumomab,    sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab,    taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab,    trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab,    votumumab, zalutumumab, alemtuzumab, veltuzumab, apolizumab,    bevacizumab, epratuzumab, tositumomab, galiximab, ibritumomab,    lumiliximab, milatuzumab, obinutuzumab, ofatumumab, CC49 and 3F8,    wherein the antibody may be further labeled or combined with a    radioisotope particle, such as indium In 111, yttrium Y 90, iodine    I-131;-   (6); JAK inhibitors selected from the group consisting of:    ruxolitinib, fedratinib, tofacitinib, baricitinib, lestaurtinib,    pacritinib, momelotinib, XL019, AZD1480, INCB039110, LY2784544,    BMS911543, and NS018;-   (7) Hedgehog inhibitors selected from the group consisting of:    saridegib;-   (8) Histone deacetylase (HDAC) inhibitors selected from the group    consisting of: pracinostat, romidepsin, vorinostat and panobinostat;-   (9) Tyrosine kinase inhibitors selected from the group consisting    of: lestaurtinib, gefitinib, erlotinib and sunitinib;-   (10) Discoidin domain receptor (DDR) inhibitors selected from the    group consisting of: the inhibitors disclosed in US2009/0142345,    US2011/0287011, WO2013/027802, WO2013/034933, and U.S. Provisional    Application No. 61/705,044;-   (11) MMP9 inhibitors selected from the group consisting of:    marimastat (BB-2516), cipemastat (Ro 32-3555), and the inhibitors    described in WO2012/027721;-   (12) LOXL inhibitors selected from the group consisting of: the    antibodies described in WO2009/017833, the antibodies described in    WO2009/017833, WO2009/035791 and WO/2011/097513;-   (13) ASK1 inhibitors selected from the group consisting of: the    compounds described in WO2011/008709 and WO/2013/112741;-   (14) PI3K inhibitors selected from the group consisting of: the    compounds described in U.S. Pat. No. 7,932,260, U.S. Provisional    Application Nos. 61/543,176; 61/581,528; 61/745,429; 61/745,437; and    61/835,333, PI3K II, TGR-1202, AMG-319, GSK2269557, X-339, X-414,    RP5090, KAR4141, XL499, OXY111A, duvelisib, IPI-443, GSK2636771, BAY    10824391, TGX221, RG-7666, CUDC-907, PQR-309, DS-7423, panulisib,    AZD-8186, CLR-457, pictilisib, neratinib, rigosertib, rigosertib    sodium, EN-3342, UCB-5857, taselisib, INCB-040093, pilaralisib,    BAY-1082439, puquitinib mesylate, XL-765, gedatolisib, VS-5584,    copanlisib, CAI orotate, alpelisib, buparlisib, BAY 80-6946, BYL719,    PX-866, RG7604, MLN1117, WX-037, AEZS-129, PA799, ZSTK474, RP-6530,    AS252424, LY294002, TG100115, LY294002, BEZ235, XL147 (SAR245408),    SAR-245409, GDC-0941, BKM120, CH5132799, XL756, MLN-1117, SF-1126,    RV-1729, sonolisib, GDC-0980, CLR-1401, perifosine and wortmannin;-   (15) BTK inhibitors selected from the group consisting of:    ibrutinib, HM71224, ONO-4059 and CC-292;-   (16) SYK inhibitors selected from the group consisting of: tamatinib    (R406), fostamatinib (R788), PRT062607, BAY-61-3606, NVP-QAB 205 AA,    R112, R343, and the compounds described in U.S. Pat. No. 8,450,321;-   (17) mTOR inhibitors selected from the group consisting of:    temsirolimus, everolimus, ridaforolimus, deforolimus, OSI-027,    AZD2014, CC-223, RAD001, LY294002, BEZ235, rapamycin, Ku-0063794,    and PP242;-   (18) AKT inhibitors selected from the group consisting of:    perifosine, MK-2206, GDC-0068 and GSK795;-   (19) MEK inhibitors selected from the group consisting of:    trametinib, selumetinib, cobimetinib, MEK162, PD-325901, PD-035901,    AZD6244, and CI-1040;-   (20) CDK inhibitors selected from the group consisting of: AT-7519,    alvocidib, palbociclib and SNS-032;-   (21) JNK inhibitors selected from the group consisting of: CC-401;-   (22) MAPK inhibitors selected from the group consisting of: VX-702,    SB203580 and SB202190;-   (23) Raf inhibitors selected from the group consisting of: PLX4720;-   (24) ROCK inhibitors selected from the group consisting of: Rho-15;-   (25) Tie2 inhibitors selected from the group consisting of:    AMG-Tie2-1;-   (26) Myo-inositol signaling inhibitors such as phospholipase C    blockers and Myoinositol analogues described in Powis, G., and    Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy    ed., Paul Workman and David Kerr, CRC press 1994, London;-   (27) Bcl-2 family protein inhibitors selected from the group    consisting of: ABT-263, ABT-199 and ABT-737;-   (28) IKK inhibitors selected from the group consisting of:    BMS-345541;-   (29) Proteasome inhibitors selected from the group consisting of:    bortezomib;-   (30) Protein kinase C (PKC) inhibitors selected from the group    consisting of: bryostatin 1 and enzastaurin;-   (31) Heat shock protein HSP90 inhibitors selected from the group    consisting of: Geldanamycin;-   (32) Combination drugs selected from the group consisting of: FR    (fludarabine, rituximab), FCR (fludarabine, cyclophosphamide,    rituximab), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus    CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), CHOP    (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP    (cyclophosphamide, vincristine and prednisone), FCM (fludarabine,    cyclophosphamide, mitoxantrone), hyperCVAD (hyperfractionated    cyclophosphamide, vincristine, doxorubicin, dexamethasone,    methotrexate, cytarabine), ICE (iphosphamide, carboplatin and    etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), and    R MCP (R MCP); and-   (33) other drugs for treating cancer selected from the group    consisting of aldesleukin, alvocidib, CHIR-12.12, ha20, tiuxetan,    PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide    vaccine, autologous human tumor-derived HSPPC-96, GTOP-99 (MyVax®),    antineoplaston AS2-1, antineoplaston A10, anti-thymocyte globulin,    beta alethine, arsenic trioxide, amifostine, aminocamptothecin,    lenalidomide, caspofungin, clofarabine, ixabepilone, cladribine,    chlorambucil, Curcumin, vinorelbine, tipifamib, tanespimycin,    sildenafil citrate, denileukin diftitox, simvastatin, epoetin alfa,    fenretinide, filgrastim, mesna, mitoxantrone, lenalidomide,    fludarabine, mycophenolate mofetil, nelarabine, octreotide,    oxaliplatin, pegfilgrastim, recombinant interleukin-12, recombinant    interleukin-11, recombinant flt3 ligand, recombinant human    thrombopoietin, sargramostim, lymphokine-activated killer cells,    omega-3 fatty acids, recombinant interferon alfa, therapeutic    allogeneic lymphocytes and cyclosporine analogs.

In a particular embodiment, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected fromibrutinib, aldesleukin, alvocidib, antineoplaston AS2-1, antineoplastonA10, anti-thymocyte globulin, amifostine trihydrate, aminocamptothecin,arsenic trioxide, beta alethine, ABT-263, ABT-199, ABT-737, BMS-345541,bortezomib, bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103,carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine(Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine,Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), denileukindiftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, Doxorubicin(Adriamycin®, Adriblastine), doxorubicin hydrochloride, enzastaurin,epoetin alfa, etoposide, everolimus (RAD001), fenretinide, filgrastim,melphalan, mesna, flavopiridol, fludarabine (Fludara), Geldanamycin (17AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, lenalidomide(Revlimid®), lymphokine-activated killer cells, melphalan, methotrexate,mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil,nelarabine, oblimersen Obatoclax, oblimersen, octreotide acetate,omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylatedliposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent),perifosine, Prednisolone, Prednisone, selicilib, recombinant interferonalfa, recombinant interleukin-12, recombinant interleukin-11,recombinant flt3 ligand, recombinant human thrombopoietin, rituximab,sargramostim, sildenafil citrate, simvastatin, sirolimus, Styrylsulphones, tacrolimus, tanespimycin, temsirolimus, thalidomide,therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, Vincristine,vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA),vorinostat, FR (fludarabine, rituximab), CHOP (cyclophosphamide,doxorubicin, vincristine, prednisone), CVP (cyclophosphamide,vincristine and prednisone), FCM (fludarabine, cyclophosphamide,mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD(hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, cytarabine), ICE (iphosphamide, carboplatinand etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone),R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM(rituximab plus FCM), R-ICE (rituximab-ICE), and R MCP (R MCP).

Any of the methods of treatment provided may be used to treat cancer atvarious stages. By way of example, the cancer stage includes but is notlimited to early, advanced, locally advanced, remission, refractory,reoccurred after remission and progressive.

In addition, the subject may be a human who is undergoing one or morestandard therapies, such as chemotherapy, radiotherapy, immunotherapy,surgery, or combination thereof. Accordingly, one or more anti-canceragents may be administered before, during, or after administration ofchemotherapy, radiotherapy, immunotherapy, surgery or combinationthereof.

The therapeutic treatments can be supplemented or combined with any ofthe abovementioned therapies with stem cell transplantation ortreatment. One example of modified approach is radioimmunotherapy,wherein a monoclonal antibody is combined with a radioisotope particle,such as indium In 111, yttrium Y 90, iodine I-131. Examples ofcombination therapies include, but are not limited to, Iodine-131tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®),Bexxar® with CHOP.

Other therapeutic procedures include peripheral blood stem celltransplantation, autologous hematopoietic stem cell transplantation,autologous bone marrow transplantation, antibody therapy, biologicaltherapy, enzyme inhibitor therapy, total body irradiation, infusion ofstem cells, bone marrow ablation with stem cell support, invitro-treated peripheral blood stem cell transplantation, umbilical cordblood transplantation, immunoenzyme technique, pharmacological study,low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery,radiation therapy, and nonmyeloablative allogeneic hematopoietic stemcell transplantation.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,and one or more additional therapeutic agents for treating cancer, foruse in a method of treating cancer.

Also provided herein is a compound of the present disclosure (e.g., acompound of Formula (I)), or a pharmaceutically acceptable salt thereof,for use in a method of treating cancer, wherein the compound or apharmaceutically acceptable salt thereof is administered simultaneously,separately or sequentially with one or more additional therapeuticagents for treating cancer.

X. KITS

The present disclosure provides a kit comprising a compound of thepresent disclosure or a pharmaceutically acceptable salt thereof. Thekit may further comprise instructions for use, e.g., for use inmodulating a toll-like receptor (e.g. TLR8), such as for use in treatinga disease, disorder, or condition. In certain embodiments the use is fortreating a HIV, HBV, or HCV infection. In certain embodiments the use isfor treating a HBV infection. The instructions for use are generallywritten instructions, although electronic storage media (e.g., magneticdiskette or optical disk) containing instructions are also acceptable.

The present disclosure also provides a pharmaceutical kit comprising oneor more containers comprising a compound of the present disclosure or apharmaceutically acceptable salt thereof. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals, which notice reflects approval by the agency for themanufacture, use or sale for human administration. Each component (ifthere is more than one component) can be packaged in separate containersor some components can be combined in one container wherecross-reactivity and shelf life permit. The kits may be in unit dosageforms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kitsmay also include multiple unit doses of the compounds and instructionsfor use and be packaged in quantities sufficient for storage and use inpharmacies (e.g., hospital pharmacies and compounding pharmacies).

XI. COMPOUND PREPARATION

Also provided are articles of manufacture comprising a unit dosage of acompound of the present disclosure or a pharmaceutically acceptable saltthereof, in suitable packaging for use in the methods described herein.Suitable packaging is known in the art and includes, for example, vials,vessels, ampules, bottles, jars, flexible packaging and the like. Anarticle of manufacture may further be sterilized and/or sealed.

The embodiments are also directed to processes and intermediates usefulfor preparing the subject compounds or pharmaceutically acceptable saltsthereof.

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith, March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 7^(th) edition,Wiley-Interscience, 2013.)

Compounds as described herein can be purified by any of the means knownin the art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography. See, e.g.,Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyderand J. J. Kirkland, John Wiley and Sons, 1979; and Thin LayerChromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 4^(th) ed., Wiley, New York 2006. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

XII. EXAMPLES

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used. Unless otherwise specified, thevariables are as defined above in reference to Formulas (I) or (J).

Representative syntheses of compounds of the present disclosure aredescribed in schemes below, and the particular examples that follow.

Scheme 1 shows a representative synthesis of the compounds of theembodiments. The methodology is compatible with a wide variety offunctionalities.

In Scheme 1, the compounds of formula A1 (where R³ and Q are as definedherein or are suitably protected derivatives of R³ and Q) in a suitablesolvent (such as tetrahydrofuran) and(R)—N-(2-amino-2-methylhexyl)acetamide are treated withN,N-diisopropylethylamine at about 80° C. to form a compound of formulaA2. The compounds of formula A2 in 2-methyl-tetrahydrofuran are treatedwith potassium carbonate followed by 2,4-dimethoxybenzylamine to form acompound of formula A3. The compounds of formula A3, in a solvent (suchas dichloromethane) are then treated with trifluoroacetic acid to form acompound of formula A4.

Scheme 2 shows a representative synthesis of the compounds of theembodiments. The methodology is compatible with a wide variety offunctionalities.

A compound of formula B1 (where Q and R³ are as defined herein or aresuitably protected derivatives of Q) is converted to a compound offormula B2, under suitable reaction conditions. For example, thecompound of formula B1 is contacted with chloroformamidine hydrochlorideunder suitable conditions to provide B2. The hydroxyl group may befurther modified, for example by introducing any suitable leaving group,such as a tosyl group, prior to contacting with R^(B)—NH₂. Further, the—OH group may be converted to a chloro group though use of a suitablereagent, such as POCl₃ and further contacted with R^(B)—NH₂.Alternatively, R^(B)—NH₂ may be directly coupled to B2 in the presenceof a suitable coupling agent, for example, BOP reagent, under suitableconditions.

Specific embodiments of formula A1 or B1 can be found in thisapplication herein, and additionally in references, such asWO2012/156498, WO2012/136834, WO2014/056953, WO2014/076221,WO2015/014815, WO2014/128189, WO2013/117615, and WO2014/023813.Intermediates corresponding to A1 or analogs thereof (includingcompounds that are outside of the variables of Formula I) may beprepared according to those references and used to prepare compounds ofthe present disclosure.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, 5^(th) edition, NewYork: Oxford University Press, 2009; Smith, March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 7^(th) edition,Wiley-Interscience, 2013.

The Examples provided herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

In the following description of the Examples, specific embodiments aredescribed. These embodiments are described in sufficient detail toenable those skilled in the art to practice certain embodiments of thepresent disclosure. Other embodiments may be utilized and logical andother changes may be made without departing from the scope of thedisclosure. The following description is, therefore, not intended tolimit the scope of the present disclosure.

The methods of the present invention generally provide a specificenantiomer or diastereomer as the desired product, although thestereochemistry of the enantiomer or diastereomer was not determined inall cases. When the stereochemistry of the specific stereocenter in theenantiomer or diastereomer is not determined, the compound is drawnwithout showing any stereochemistry at that specific stereocenter eventhough the compound can be substantially enantiomerically ordiastereomerically pure.

Example 1

Synthesis of (R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1a)

To a mixture of (R)-(−)-2-phenylglycinol (23.6 g, 172 mmol, supplied bySigma-Aldrich, 99% ee) and molecular sieves (86 g) in2,2,2-trifluoroethanol (500 mL) was added ethyl pyruvate (19.2 mL, 172mmol, supplied by Sigma Aldrich) and the mixture heated to reflux. After24 h, the reaction was cooled to rt, filtered through Celite, washedwith EtOAc, and concentrated in vacuo. The residue was subjected tosilica gel chromatography equipped with an ELSD eluting withhexanes-EtOAc to provide 1a. LC/MS (ESI) calculated for C₁₁H₁₂NO₂: m/z190.08, found 189.92 [M+H]⁺; t_(R)=0.88 min. on LC/MS Method A. ¹H NMR(400 MHz, Chloroform-d) δ 7.45-7.38 (m, 2H), 7.38-7.32 (m, 3H), 4.85(ddd, J=10.9, 4.6, 2.4 Hz, 1H), 4.57 (dd, J=11.6, 4.5 Hz, 1H), 4.26 (dd,J=11.6, 10.9 Hz, 1H), 2.41 (d, J=2.4 Hz, 3H).

Synthesis of (3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one (1b)

To compound 1a (14.84 g, 78.43 mmol) in THF (500 mL) at −78° C. underargon was added boron trifluoride diethyl etherate (20.5 mL, 161.11mmol) over 30 min. After 90 min, n-butylmagnesium chloride solution(83.0 mL, 166 mmol, 2.0 M in THF) was added over 30 min. After 2 h, thereaction was warmed to rt and quenched with saturated NH₄Cl_((aq)) (300mL). The mixture was diluted with water (200 mL) and extracted withEtOAc (300 mL×3). The organic extracts were washed with water (500mL×3), brine (300 mL), dried over Na₂SO₄, and concentrated in vacuo. Theresidue was dissolved in DCM (150 mL), heated, and the insolublematerial was removed by filtration. The filtrate was concentrated invacuo and the residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc to provide compound 1b. LC/MS (ESI) calculated forC₁₅H₂₂NO₂: m/z 248.16, found 248.02 [M+H]⁺; t_(R)=1.07 min. on LC/MSMethod A. ¹H NMR (400 MHz, Chloroform-d) δ 7.51-7.28 (m, 5H), 4.44-4.31(m, 2H), 4.27 (t, J=11.5 Hz, 1H), 2.03 (ddd, J=13.8, 11.4, 4.7 Hz, 1H),1.74 (td, J=12.2, 11.2, 4.1 Hz, 2H), 1.46 (s, 3H), 1.43-1.20 (m, 4H),0.99-0.85 (m, 3H).

Synthesis of(R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol (1c)

To compound 1b (14.01 g, 56.64 mmol) in THF (100 mL) at 0° C. was addedLiBH₄ solution (57 mL, 114 mmol, 2.0 M in THF) and the reaction wasallowed to warm to rt. After 2 h, the mixture was cooled to 0° C. andquenched with water (500 mL). The mixture was separated and the aqueouswas extracted with EtOAc (300 mL×3). The combined organics were washedwith water (500 mL) and brine (100 mL), dried over Na₂SO₄, andconcentrated under reduced pressure to provide 1c. LC/MS (ESI)calculated for C₁₅H₂₆NO₂: m/z 252.19, found 252.05 [M+H]⁺; t_(R)=0.68min. on LC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ 7.33-7.22 (m,5H), 3.85 (dd, J=9.4, 4.6 Hz, 1H), 3.60 (dd, J=10.5, 4.6 Hz, 1H), 3.43(dd, J=10.5, 9.4 Hz, 1H), 3.37 (d, J=11.2 Hz, 1H), 3.14 (d, J=11.1 Hz,1H), 2.31 (s, 3H), 1.37-1.23 (m, 1H), 1.23-1.00 (m, 4H), 0.96 (s, 1H),0.78 (t, J=6.9 Hz, 3H).

Synthesis of (R)-2-amino-2-methylhexan-1-ol (1d)

To a mixture of compound 1c (14.24 g, 56.65 mmol) and 20% Pd(OH)₂ oncarbon (2.85 g) in EtOH (210 mL) was added HCl solution (21.5 mL, 86.0mmol, 4 M in dioxane) The resulting mixture was purged with H₂ gas andthen stirred under H₂ atmosphere at 70° C. After 10 h, the reactionmixture was cooled to rt, filtered through Celite, rinsed with EtOH (50mL), and concentrated in vacuo. The residue was co-evaporated withtoluene (50 mL×1) to provide compound 1d as an HCl salt. LC/MS (ESI)calculated for C₇H₁₈NO: m/z 132.13, found 131.90 [M+H]⁺; t_(R)=0.42 min.on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 3.54 (d, J=11.4 Hz,1H), 3.46 (d, J=11.5 Hz, 1H), 1.65 (ddd, J=14.0, 11.0, 5.8 Hz, 1H), 1.57(dt, J=13.8, 5.4 Hz, 1H), 1.44-1.26 (m, 4H), 1.24 (s, 3H), 0.95 (t,J=7.0 Hz, 3H).

Synthesis of (R)-tert-butyl (1-hydroxy-2-methylhexan-2-yl)carbamate (1e)

To a solution of 1d (1 g, 7.6 mmol) in THF (35 mL) was added sat.NaHCO_(3(aq)) (35 mL) followed by di-tert-butyl dicarbonate (3.33 g,15.24 mmol). After 24 h, the organic solvents were removed in vacuo. Theresulting slurry was diluted with water (50 mL), extracted with EtOAc(100 mL), washed with brine (10 mL), dried over Na₂SO₄, and concentratedin vacuo. The residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc to provide 1e. LC/MS (ESI) calculated for C₁₂H₂₅NO₃:m/z 232.18, found 231.61 [M+H]⁺; t_(R)=1.09 min. on LC/MS Method A. ¹HNMR (400 MHz, Chloroform-d) δ 3.64 (d, J=11.4 Hz, 1H), 3.59 (d, j=11.5Hz, 1H), 1.75-1.65 (m, 1H), 1.56-1.45 (m, 1H), 1.43 (s, 9H), 1.37-1.27(m, 4H), 1.16 (s, 3H), 0.91 (t, J=7.0 Hz, 3H).

Synthesis of (R)-tert-butyl (2-methyl-1-oxohexan-2-yl)carbamate (1f)

To a solution of 1e (2.1 g, 9.0 mmol) in DCM (100 mL) was addedDess-Martin periodinane (5.7 g, 14 mmol). After 2 h the reaction wasquenched with sat. Na₂S₂O_(3(aq)) (75 mL). The mixture was separated andthe aqueous layer was extracted with DCM (100 mL). The combined organicswere washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄,then filtered and concentrated in vacuo. The residue was subjected tosilica gel chromatography eluting with hexanes-EtOAc to provide 1f.LC/MS (ESI) calculated for C₈H₁₅NO₃: m/z 231.17, found 173.75[M+H−(t-Bu)]⁺; t_(R)=1.18 min. on LC/MS Method A. ¹H NMR (400 MHz,Chloroform-d) δ 9.36 (s, 1H), 1.98-1.78 (m, 1H), 1.70-1.61 (m, 1H), 1.44(s, 9H), 1.35 (s, 3H), 1.34-1.26 (m, 4H), 0.89 (t, J=7.1 Hz, 3H).

Synthesis of (R)-tert-butyl(1-(benzylamino)-2-methylhexan-2-yl)carbamate (1g)

To a solution of 1f (1.9 g, 8.4 mmol) in dry MeOH (50 mL) was addedbenzylamine (1.0 mL, 8.35 mmol). After 18 h, sodium borohydride (500 mg,13 mmol) was added portionwise. After 60 minutes, the mixture wasconcentrated in vacuo. The resulting residue was dissolved in EtOAc (50mL), washed with 1M NaOH_((aq)) (50 mL), 10% aqueous Rochelle's saltsolution (50 mL, solid supplied by Sigma-Aldrich), and brine (50 mL),dried over Na₂SO₄, then filtered and concentrated in vacuo to afford 1g.LC/MS (ESI) calculated for C₁₉H₃₂N₂O₂: m/z 321.25, found 321.03 [M+H]⁺;t_(R)=0.94 min. on LC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ7.35-7.31 (m, 5H), 3.86-3.78 (m, 2H), 2.82-2.69 (m, 1H), 2.66-2.54 (m,1H), 1.42 (s, 9H), 1.33-1.26 (m, 3H), 1.25 (s, 3H), 1.21-1.17 (m, 1H),0.89 (t, J=7.2 Hz, 3H).

Synthesis of (R)-tert-butyl(1-(N-benzylacetamido)-2-methylhexan-2-yl)carbamate (1h)

To a solution of 1g (2.2 g, 6.9 mmol) in THF (50 mL) was addedN,N-diisopropylethylamine (2.4 mL, 14 mmol) followed by acetyl chloride(0.75 mL, 11 mmol). After 60 minutes, the mixture was diluted with EtOAc(150 mL), washed with sat. NaHCO_(3(aq)) (100 mL) and brine (100 mL),dried over Na₂SO₄, then filtered and concentrated in vacuo. The residuewas subjected to silica gel chromatography eluting with hexanes-EtOAc toprovide 1h. LC/MS (ESI) calculated for C₂₁H₃₄N₂O₃: m/z 363.26, found362.82 [M+H]⁺; t_(R)=1.32 min. on LC/MS Method A. ¹H NMR (400 MHz,Chloroform-d) δ 7.39-7.32 (m, 2H), 7.32-7.28 (m, 1H), 7.13-7.08 (m, 2H),4.64 (dd, J=17.4, 8.1 Hz, 2H), 2.12 (s, 3H), 1.78-1.65 (m, 2H), 1.41 (s,9H), 1.34-1.22 (m, 7H), 0.89 (t, J=7.0 Hz, 3H).

Synthesis of (R)—N-(2-amino-2-methylhexyl)acetamide (1i)

To a solution of 1h (2.0 g, 5.4 mmol) in EtOH (55 mL) and HCl solution(2 mL, 4 M in dioxane) that was purged with Ar was added palladiumhydroxide on carbon (2.0 g, 20 wt %). The mixture was purged with H₂ andheated to 70° C. After 24 h, the reaction mixture was filtered throughCelite, rinsed with EtOAc, and concentrated in vacuo to afford 1i as anHCl salt. LC/MS (ESI) calculated for C₉H₂₀N₂O: m/z 173.16, found 172.92[M+H]⁺; t_(R)=0.50 min. on LC/MS Method A. ¹H NMR (400 MHz, MeOH-d₄) δ3.34 (d, J=4.1 Hz, 2H), 2.02 (s, 3H), 1.66-1.57 (m, 2H), 1.45-1.33 (m,4H), 1.29 (s, 3H), 0.98 (t, J=6.9 Hz, 3H).

Synthesis of(R)—N-(2-((2-chloroquinazolin-4-yl)amino)-2-methylhexyl)acetamide (1j)

To a solution of 1i (202 mg, 0.97 mmol) and 2,4-dichloroquinazoline (500mg, 0.97 mmol, supplied by AstaTech, Inc.) in THF (4 mL) was addedN,N-diisopropylethylamine (0.67 mL, 3.87 mmol). After stirring at 75° C.for 22 h, the reaction was cooled to rt, diluted with EtOAc (10 mL),washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, thenfiltered and concentrated in vacuo. The residue was subjected to silicagel chromatography eluting with hexanes-EtOAc to provide 1j as a mixtureof isomers. LC/MS (ESI) calculated for C₁₇H₂₃ClN₄O: m/z 335.15, found335.20 [M+H]⁺; t_(R)=1.08 min. on LC/MS Method A. ¹H NMR (400 MHz,Chloroform-d) δ 9.27 (s, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.84 (d, J=8.3 Hz,1H), 7.76-7.67 (m, 4H), 7.48 (ddt, J=8.4, 5.3, 2.6 Hz, 3H), 6.59 (s,1H), 5.65 (s, 1H), 3.83 (dd, J=14.0, 5.0 Hz, 2H), 3.69 (dd, J=14.1, 4.1Hz, 1H), 3.20 (dd, J=14.5, 6.1 Hz, 1H), 2.25 (t, J=12.7 Hz, 1H), 2.13(s, 2H), 2.09 (s, 3H), 2.02-1.88 (m, 2H), 1.77-1.64 (m, 2H), 1.57 (d,J=4.6 Hz, 5H), 1.39 (s, 4H), 1.36-1.27 (m, 10H), 0.88 (td, J=7.2, 6.8,2.8 Hz, 9H).

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)quinazolin-4-yl)amino)-2-methylhexyl)acetamide(1k)

To a solution of 1j (40.6 mg, 0.12 mmol) in 2-MeTHF (2 mL) was addedpotassium carbonate (34.5 mg, 0.24 mmol) followed by2,4-dimethoxybenzylamine (0.04 mL, 0.24 mmol, supplied bySigma-Aldrich). After stirring at 80° C. for 18 h, the reaction wascooled to rt, diluted with EtOAc (10 mL), washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was purified by preparative HPLC (Gemini 10u C18110A, Axia; 25% aq. acetonitrile-70% aq. acetonitrile, over 20 min.gradient) to provide 1k as a TFA salt. LC/MS (ESI) calculated forC₂₆H₃₅N₅O₃: m/z 466.27, found 466.39 [M+H]⁺; t_(R)=0.99 min. on LC/MSMethod A. ¹H NMR (400 MHz, Chloroform-d) δ 9.51 (s, 1H), 8.72 (s, 1H),7.85 (d, J=7.9 Hz, 1H), 7.65-7.57 (m, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.30(dd, J=7.8, 2.6 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.43 (d, J=2.6 Hz, 1H),6.37 (d, J=8.4 Hz, 1H), 6.29 (s, 1H), 4.63 (d, J=5.4 Hz, 2H), 3.91-3.83(m, 1H), 3.82 (d, J=2.2 Hz, 3H), 3.76 (d, J=2.2 Hz, 3H), 3.01 (d, J=14.6Hz, 1H), 2.19 (d, J=13.0 Hz, 1H), 2.11 (d, J=2.8 Hz, 3H), 1.79 (t,J=13.1 Hz, 1H), 1.47 (d, J=2.8 Hz, 3H), 1.21-1.06 (m, 4H), 0.83 (t,J=6.7 Hz, 3H). ¹⁹F NMR (377 MHz, Chloroform-d) δ −76.19.

Synthesis of(R)—N-(2-((2-aminoquinazolin-4-yl)amino)-2-methylhexyl)acetamide (1)

To 1k (3.3 mg, 0.01 mmol) in DCM (1 mL) was added TFA (1.5 mL). After 4h, the reaction mixture was concentrated in vacuo and coevaporated withMeOH (3×20 mL). The residue was suspended in MeOH and filtered. Thesolution was concentrated in vacuo to afford 1 as its TFA salt. LC/MS(ESI) calculated for C₁₇H₂₅N₅O: m/z 316.21, found 316.22 [M+H]⁺;t_(R)=0.76 min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.57(t, J=5.9 Hz, 1H), 8.18-8.01 (m, 1H), 7.78 (ddd, J=8.4, 7.4, 1.2 Hz,1H), 7.42 (ddd, J=20.7, 9.8, 4.6 Hz, 2H), 3.89 (dd, J=14.3, 5.8 Hz, 1H),3.34 (d, J=6.5 Hz, 1H), 2.23-2.10 (m, 2H), 2.03 (s, 3H), 1.57 (s, 3H),1.36-1.31 (m, 4H), 0.91 (t, J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d₄) δ −77.51.

Example 2

Synthesis of(R)—N-(2-((2-chloro-7-fluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide(2a)

To a solution of 1i (80.8 mg, 0.39 mmol) and2,4-dichloro-7-fluoroquinazoline (84.8 mg, 0.39 mmol, supplied byAstaTech, Inc.) in THF (1.6 mL) was added N,N-diisopropylethylamine(0.27 mL, 1.55 mmol). After stirring at 75° C. for 18 h, the reactionwas cooled to rt, diluted with EtOAc (10 mL), washed with water (10 mL)and brine (10 mL), dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc to provide 2a. LC/MS (ESI) calculated forC₁₇H₂₂ClFN₄O: m/z 353.15, found 353.17 [M+H]⁺; t_(R)=1.36 min. on LC/MSMethod A.

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide(2b)

To a solution of 2a (64 mg, 0.18 mmol) in 2-MeTHF (2 mL) was addedpotassium carbonate (52.7 mg, 0.36 mmol) followed by2,4-dimethoxybenzylamine (0.06 mL, 0.36 mmol). After stirring at 80° C.for 4 d, the reaction was cooled to rt, diluted with EtOAc (10 mL),washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, thenfiltered and concentrated in vacuo. The residue was subjected to silicagel chromatography eluting with hexanes-EtOAc to provide 2b. LC/MS (ESI)calculated for C₂₆H₃₄FN₅O₃: m/z 484.27, found 484.19 [M+H]⁺; t_(R)=1.29min. on LC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ 7.59 (dd,J=9.0, 5.9 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 6.99 (d, J=9.7 Hz, 1H), 6.80(td, J=8.6, 2.6 Hz, 1H), 6.45 (d, J=2.3 Hz, 1H), 6.39 (dd, J=8.3, 2.4Hz, 1H), 4.63-4.51 (m, 2H), 3.86-3.79 (m, 4H), 3.78 (s, 3H), 3.21 (dd,J=14.1, 6.4 Hz, 1H), 2.10-2.04 (m, 1H), 2.03 (s, 3H), 1.95-1.83 (m, 1H),1.45 (s, 3H), 1.25-1.17 (m, 4H), 0.84 (t, J=7.1 Hz, 3H). ¹⁹F NMR (377MHz, Chloroform-d) δ −108.10.

Synthesis of(R)—N-(2-((2-amino-7-fluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide(2)

To 2b (36.5 mg, 0.08 mmol) was added TFA (3 mL). After 90 min, thereaction mixture was concentrated in vacuo and coevaporated with MeOH(3×20 mL). The residue was suspended in MeOH and filtered. The solutionwas concentrated in vacuo to afford 2 as its TFA salt. LC/MS (ESI)calculated for C₁₇H₂₄FN₅O: m/z 334.20, found 334.19 [M+H]⁺; t_(R)=0.99min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.77 (s, 1H),8.18 (dd, J=9.1, 5.4 Hz, 1H), 7.22-7.11 (m, 2H), 3.86 (d, J=14.2 Hz,1H), 3.33 (d, J=14.1 Hz, 1H), 2.12 (t, J=7.9 Hz, 2H), 2.02 (s, 3H), 1.55(s, 3H), 1.37-1.26 (m, 4H), 0.90 (t, J=7.0 Hz, 3H).

Example 3

Synthesis of(R)—N-(2-((2-chloro-6,7-difluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide(3a)

To a solution of 1i (80.8 mg, 0.39 mmol) and2,4-dichloro-6,7-difluoroquinazoline (90.1 mg, 0.39 mmol, supplied byMatrix Scientific) in THF (1.6 mL) was added N,N-diisopropylethylamine(0.27 mL, 0.15 mmol). After stirring at 75° C. for 18 h, the reactionwas cooled to rt, diluted with EtOAc (10 mL), washed with water (10 mL)and brine (10 mL), dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc to provide 3a. LC/MS (ESI) calculated forC₁₇H₂₁ClF₂N₄O: m/z 371.14, found 371.12 [M+H]⁺; t_(R)=1.51 min. on LC/MSMethod A.

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)-6,7-difluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide(3b)

To a solution of 3a (78.9 mg, 0.21 mmol) in 2-MeTHF (2 mL) was addedpotassium carbonate (61.5 mg, 0.43 mmol) followed by2,4-dimethoxybenzylamine (0.06 mL, 0.43 mmol). After stirring at 80° C.for 4 d, the reaction was cooled to rt, diluted with EtOAc (10 mL),washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, thenfiltered and concentrated in vacuo. The residue was subjected to silicagel chromatography eluting with hexanes-EtOAc to provide 3b. LC/MS (ESI)calculated for C₂₆H₃₃F₂N₅O₃: m/z 502.26, found 502.25 [M+H]⁺; t_(R)=1.32min. on LC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ 7.44 (dd,J=10.9, 8.4 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.10 (dd, J=11.5, 7.8 Hz,1H), 6.75 (s, 1H), 6.45 (d, J=2.3 Hz, 1H), 6.40 (dd, J=8.3, 2.4 Hz, 1H),6.09 (s, 1H), 5.29 (s, 1H), 4.56 (d, J=6.0 Hz, 2H), 3.85-3.78 (m, 4H),3.78 (s, 3H), 3.17 (dd, J=14.2, 6.4 Hz, 1H), 2.12-2.06 (m, 1H), 2.05 (s,3H), 1.94-1.83 (m, 1H), 1.46 (s, 3H), 1.27-1.19 (m, 4H), 0.85 (t, J=6.4Hz, 3H). ¹⁹F NMR (377 MHz, Chloroform-d) δ −131.08, −144.04.

Synthesis of(R)—N-(2-((2-amino-6,7-difluoroquinazolin-4-yl)amino)-2-methylhexyl)acetamide(3)

To 3b (32.9 mg, 0.07 mmol) was added TFA (3 mL). After 1 h, the reactionmixture was concentrated in vacuo and coevaporated with MeOH (3×20 mL).The residue was suspended in MeOH and filtered. The solution wasconcentrated in vacuo to afford 3 as its TFA salt. LC/MS (ESI)calculated for C₁₇H₂₃F₂N₅O: m/z 352.19, found 352.17 [M+H]⁺; t_(R)=1.03min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.70 (s, 1H),8.17 (dd, J=11.0, 7.8 Hz, 1H), 7.36 (dd, J=10.6, 6.9 Hz, 1H), 3.87 (d,J=14.2 Hz, 1H), 3.38 (d, J=14.2 Hz, 1H), 2.17 (ddd, J=13.8, 9.7, 6.3 Hz,1H), 2.06 (dd, J=10.7, 5.3 Hz, 1H), 2.02 (s, 3H), 1.54 (s, 3H),1.35-1.27 (m, 4H), 0.91 (t, J=6.9 Hz, 3H). ¹⁹F NMR (377 MHz,Methanol-d₄) δ −77.84, ⁻127.42-⁻129.14 (m), −141.96 (ddd, J=21.6, 10.9,6.8 Hz).

Example 4

Synthesis of(R)—N-(2-((2-chloropyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(4a)

To a solution of 1i (80.8 mg, 0.39 mmol) and2,4-dichloropyrido[3,4-d]pyrimidine (78.1 mg, 0.39 mmol, supplied byAstaTech, Inc.) in THF (1.6 mL) was added N,N-diisopropylethylamine(0.27 mL, 1.5 mmol). After stirring at 75° C. for 18 h, the reaction wascooled to rt, diluted with EtOAc (10 mL), washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc to provide 4a. LC/MS (ESI) calculated forC₁₆H₂₂ClN₅O: m/z 336.15, found 336.12 [M+H]⁺; t_(R)=1.14 min. on LC/MSMethod A.

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(4b)

To a solution of 4a (43.7 mg, 0.13 mmol) in 2-MeTHF (2 mL) was addedpotassium carbonate (36.3 mg, 0.26 mmol) followed by2,4-dimethoxybenzylamine (0.04 mL, 0.26 mmol). After stirring at 80° C.for 18 h, the reaction was cooled to rt, diluted with EtOAc (10 mL),washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, thenfiltered and concentrated in vacuo. The residue was subjected to silicagel chromatography eluting with hexanes-EtOAc to provide 4b. LC/MS (ESI)calculated for C₂₅H₃₄N₆O₃: m/z 467.27, found 467.21 [M+H]⁺; t_(R)=1.11min. on LC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ 8.80 (s, 1H),8.24 (d, J=5.5 Hz, 1H), 7.44 (d, J=5.5 Hz, 1H), 7.22 (s, 1H), 6.46 (d,J=2.3 Hz, 1H), 6.40 (d, J=8.5 Hz, 1H), 6.16 (s, 1H), 4.60 (d, J=6.0 Hz,2H), 3.83 (s, 5H), 3.78 (s, 3H), 3.14 (dd, J=14.5, 6.3 Hz, 1H), 2.13 (t,J=14.2 Hz, 1H), 2.08 (s, 3H), 2.04 (s, 3H), 1.93-1.82 (m, 2H), 1.48 (s,3H), 1.23 (m, 4H), 0.85 (t, J=6.7 Hz, 3H).

Synthesis of(R)—N-(2-((2-aminopyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(4)

To 4b (16.8 mg, 0.04 mmol) was added TFA (3 mL). After 24 h, thereaction mixture was concentrated in vacuo and coevaporated with MeOH(3×20 mL). The residue was suspended in MeOH and filtered. The solutionwas concentrated in vacuo to afford 4 as its TFA salt. LC/MS (ESI)calculated for C₁₆H₂₄N₆O: m/z 317.20, found 317.17 [M+H]⁺; t_(R)=0.85min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 9.17 (s, 1H),8.79 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.05 (d, J=5.5 Hz, 1H), 3.87 (d,J=14.3 Hz, 1H), 3.36 (d, J=14.3 Hz, 1H), 2.23-2.07 (m, 2H), 2.02 (s,3H), 1.57 (s, 3H), 1.38-1.31 (m, 4H), 0.91 (t, J=6.8 Hz, 3H). ¹⁹F NMR(377 MHz, Methanol-d₄) δ −77.93.

Example 5

Synthesis of(R)—N-(2-((2-chloropyrido[2,3-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(5a)

To a solution of 1i (106 mg, 0.50 mmol) and2,4-dichloropyrido[2,3-d]pyrimidine (100 mg, 0.50 mmol, supplied byCombi-Blocks) in THF (2 mL) was added N,N-diisopropylethylamine (0.35mL, 2.0 mmol). After stirring at 80° C. for 2 h, the reaction was cooledto rt, diluted with EtOAc (15 mL), washed with water (15 mL) and brine(15 mL), dried over Na₂SO₄, then filtered and concentrated in vacuo. Theresidue was subjected to silica gel chromatography eluting withhexanes-EtOAc to provide 5a. LC/MS (ESI) calculated for C₁₆H₂₂ClN₅O: m/z336.15, found 336.21 [M+H]⁺; t_(R)=0.94 min. on LC/MS Method A. ¹H NMR(400 MHz, Chloroform-d) δ 8.96 (dd, J=4.4, 1.8 Hz, 1H), 8.49 (s, 1H),8.38 (dd, J=8.2, 1.8 Hz, 1H), 7.41 (dd, J=8.2, 4.5 Hz, 1H), 6.72 (t,J=6.9 Hz, 1H), 3.85 (dd, J=14.5, 6.7 Hz, 1H), 3.14 (dd, J=14.5, 6.3 Hz,1H), 2.36 (td, J=13.4, 12.7, 4.4 Hz, 1H), 2.16 (s, 3H), 1.92 (td,J=13.8, 12.8, 3.9 Hz, 1H), 1.59 (s, 3H), 1.41-1.22 (m, 4H), 0.86 (t,J=7.2 Hz, 3H).

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[2,3-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(5b)

To a solution of 5a (128.5 mg, 0.38 mmol) in 2-MeTHF (2.5 mL) was addedpotassium carbonate (107 mg, 0.77 mmol) followed by2,4-dimethoxybenzylamine (0.12 mL, 0.77 mmol). After stirring at 80° C.for 18 h, the reaction was cooled to rt, diluted with EtOAc (15 mL),washed with water (15 mL) and brine (15 mL), dried over Na₂SO₄, thenfiltered and concentrated in vacuo. The residue was subjected to silicagel chromatography eluting with hexanes-EtOAc to provide 5b. LC/MS (ESI)calculated for C₂₅H₃₄N₆O₃: m/z 467.27, found 467.40 [M+H]⁺; t_(R)=0.90min. on LC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H),8.17 (s, 1H), 7.17 (s, 1H), 7.00 (dd, J=8.1, 4.6 Hz, 1H), 6.46 (d, J=2.4Hz, 1H), 6.41 (d, J=8.4 Hz, 1H), 4.76-4.48 (m, 2H), 3.85-3.80 (m, 1H),3.79 (s, 6H), 3.15 (dd, J=14.3, 6.1 Hz, 1H), 2.18 (s, 1H), 2.11 (s, 3H),1.84 (s, 1H), 1.51 (s, 3H), 1.17 (s, 4H), 0.83 (s, 3H).

Synthesis of(R)—N-(2-((2-aminopyrido[2,3-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(5)

To 5b (168.5 mg, 0.36 mmol) was added TFA (3 mL). After 24 h, thereaction mixture was concentrated in vacuo and coevaporated with MeOH(3×20 mL). The residue was suspended in MeOH and filtered. The solutionwas concentrated in vacuo to afford 5 as its TFA salt. LC/MS (ESI)calculated for C₁₆H₂₄N₆O: m/z 317.20, found 317.24 [M+H]⁺; t_(R)=0.64min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 9.05 (s, 1H),8.73 (dd, J=4.7, 1.6 Hz, 1H), 8.55 (dd, J=8.2, 1.6 Hz, 1H), 7.46 (dd,J=8.2, 4.7 Hz, 1H), 3.87 (dd, J=14.3, 5.3 Hz, 1H), 3.40-3.33 (m, 1H),2.23-2.04 (m, 2H), 2.02 (s, 3H), 1.57 (s, 3H), 1.39-1.28 (m, 4H), 0.92(t, J=6.9 Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d₄) δ −77.93.

Example 6

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-2-methylhexyl)acetamide(6a)

A solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (supplied byAstatech, Inc.) (100 mg, 0.49 mmol) in THF (10 mL) was treated with 1i,(200 mg, 0.95 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.15 mmol).After the mixture was stirred under reflux for 12 h,2,4-dimethoxybenzylamine (0.38 mL, 2.5 mmol) andN,N-diisopropylethylamine (0.13 mL, 0.75 mmol) were added, and themixture was heated to 115° C. for 2 h in a microwave reactor. After thistime, the reaction was cooled to rt, diluted with EtOAc (100 mL), washedwith water (100 mL), brine (100 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was subjected to silica gelflash chromatography eluting with 0-100% EtOAc in hexanes to provide 6a.LCMS (m/z): 470.21 [M+H]⁺.

Synthesis of(R)—N-(2-((2-amino-5,6,7,8-tetrahydroquinazolin-4-yl)amino)-2-methylhexyl)acetamide(6)

6a (60 mg, 0.133 mmol) was dissolved in TFA (3 mL). After 60 minutes,the mixture was concentrated in vacuo. The residue was taken up in MeOH,filtered and concentrated in vacuo, to give the title compound 6 as itsTFA salt.

¹H NMR (400 MHz, MeOH-d₄) 8.65 (dd, J=4.3, 1.5 Hz, 1H), 7.86-7.73 (m,2H), 4.68-4.55 (m, 4H), 3.59 (dd, J=13.9, 4.3 Hz, 4H), 3.34-3.23 (m,3H), 1.88 (s, 3H), 1.78-1.67 (m, 2H), 1.39 (ddd, J=7.7, 5.1, 2.4 Hz,4H), 0.91 (ddt, J=8.3, 4.7, 3.0 Hz, 3H).

¹⁹F NMR (377 MHz, MeOH-d4) δ −77.7.

LC/MS 320.15 [M+H]⁺; t_(R)=0.91 min. (LC/MS HPLC method A).

Example 7

Synthesis of 2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (7a)

To a solution of tert-butyl2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (500mg, 1.64 mmol, supplied by AstaTech, Inc.) in DCM (10 mL) was added HClsolution (1 mL, 4.0 mmol, 4 M in dioxane). After 3 d, the reaction wasconcentrated in vacuo to afford 7a as an HCl salt. LC/MS (ESI)calculated for C₇H₇Cl₂N₃: m/z 204.00, found 204.00 [M+H]⁺; t_(R)=0.25min. on LC/MS Method A.

Synthesis of1-(2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one(7b)

To 7a (401.9 mg, 1.64 mmol) in THF (20 mL) was added triethylamine (0.55mL, 3.95 mmol) followed by acetyl chloride (0.15 mL, 2.11 mmol). After60 min, the mixture was concentrated in vacuo. The residue was dilutedwith EtOAC (30 mL) and washed with sat. NaHCO_(3(aq)) (30 mL) and brine(30 mL). The combined aqueous was extracted with EtOAc (50 mL). Thecombined organics were dried over Na₂SO₄ and concentrated in vacuo toafford 7b LC/MS (ESI) calculated for C₉H₉Cl₂N₃O: m/z 246.01, found246.14 [M+H]⁺; t_(R)=0.68 min. on LC/MS Method A.

Synthesis of(R)—N-(2-((6-acetyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(7c)

To a solution of 7b (420.7 mg, 1.64 mmol) and 1i (363.9 mg, 1.64 mmol)in NMP (6.5 mL) was added N,N-diisopropylethylamine (0.60 mL, 3.29mmol). After stirring at 150° C. for 18 h, the reaction was cooled tort, diluted with EtOAc (30 mL) and washed with water (30 mL). Theaqueous was extracted with EtOAc (30 mL). The Combined organics werewashed with brine (3×50 mL), dried over Na₂SO₄, then filtered andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with EtOAc-MeOH to provide 7c as a mixture ofproducts. LC/MS (ESI) calculated for C₁₈H₂₈ClN₅O₂: m/z 382.19, found382.29 [M+H]⁺; t_(R)=0.88 min. on LC/MS Method A.

Synthesis of(R)—N-(2-((6-acetyl-2-((2,4-dimethoxybenzyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(7d)

To a solution of 7c (418.1 mg, 1.10 mmol) in 2-MeTHF (10 mL) was addedpotassium carbonate (303.9 mg, 2.19 mmol) followed by2,4-dimethoxybenzylamine (0.82 mL, 5.47 mmol) in a sealed vessel. Afterstirring at 150° C. for 18 h, the reaction was cooled to rt, dilutedwith EtOAc (20 mL) and washed with water (15 mL) and brine (15 mL). Thecombined aqueous was extracted with EtOAc (50 mL). The combined organicswere dried over Na₂SO₄, then filtered and concentrated in vacuo. Theresidue was purified by preparative HPLC (Gemini 10u C18 110A, Axia; 25%aq. acetonitrile-45% aq. acetonitrile, over 12 min. gradient) to provide7d as a TFA salt. LC/MS (ESI) calculated for C₂₇H₄₀N₆O₄: m/z 513.31,found 513.46 [M+H]⁺; t_(R)=0.88 min. on LC/MS Method A. ¹H NMR (400 MHz,Chloroform-d) δ 9.12 (dt, J=70.2, 5.8 Hz, 1H), 7.54 (d, J=168.2 Hz, 1H),7.07 (d, J=8.3 Hz, 1H), 6.46-6.40 (m, 1H), 6.37 (dt, J=8.3, 2.1 Hz, 1H),6.16 (dt, J=72.4, 6.6 Hz, 1H), 4.52 (d, J=5.8 Hz, 2H), 4.41-4.22 (m,1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.69 (dt, J=21.6, 6.8 Hz, 3H), 2.97(ddd, J=38.6, 14.6, 6.3 Hz, 1H), 2.82 (t, J=5.1 Hz, 1H), 2.73 (t, J=6.0Hz, 1H), 2.21 (d, J=34.6 Hz, 3H), 2.07 (d, J=2.4 Hz, 3H), 2.05-1.97 (m,1H), 1.81-1.67 (m, 1H), 1.39 (d, J=11.7 Hz, 3H), 1.21-0.98 (m, 4H), 0.85(t, J=6.6 Hz, 3H). ¹⁹F NMR (377 MHz, Chloroform-d) δ −76.33.

Synthesis of(R)—N-(2-((6-acetyl-2-amino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(7)

To 7d (53.6 mg, 0.11 mmol) was added TFA (3 mL). After 3 h, the reactionmixture was concentrated in vacuo and coevaporated with MeOH (3×20 mL).The residue was suspended in MeOH and filtered. The solution wasconcentrated in vacuo to afford 7 as its TFA salt. LC/MS (ESI)calculated for C₁₈H₃₀N₆O₂: m/z 363.24, found 363.36 [M+H]⁺; t_(R)=0.65min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 7.53 (d, J=154.6Hz, 1H), 4.41-4.20 (m, 2H), 4.02-3.60 (m, 5H), 3.20 (dd, J=31.3, 14.2Hz, 1H), 2.70 (dt, J=47.8, 5.9 Hz, 2H), 2.22 (d, J=18.5 Hz, 3H),2.17-2.07 (m, 1H), 2.02 (d, J=5.5 Hz, 3H), 2.00-1.92 (m, 1H), 1.49 (d,J=15.4 Hz, 3H), 1.38-1.15 (m, 4H), 0.91 (td, J=7.1, 3.3 Hz, 3H). ¹⁹F NMR(377 MHz, Methanol-d₄) δ −77.86.

Example 8

Synthesis of 2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (8a)

To a solution of tert-butyl2,4-dichloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (500mg, 1.64 mmol, supplied by AstaTech, Inc.) in DCM (10 mL) was added HClsolution (2 mL, 8.0 mmol, 4 M in dioxane). After 18 h, the reaction wasconcentrated in vacuo to afford 8a as an HCl salt. LC/MS (ESI)calculated for C₇H₇Cl₂N₃: m/z 204.00, found 204.00 [M+H]⁺; t_(R)=0.38min. on LC/MS Method A.

Synthesis of1-(2,4-dichloro-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)ethan-1-one(8b)

To 8a in THF (20 mL) was added triethylamine (0.55 mL, 3.95 mmol)followed by acetyl chloride (0.14 mL, 1.97 mmol). After 60 min, themixture was concentrated in vacuo. The residue was diluted with EtOAC(30 mL) and washed with sat. NaHCO_(3(aq)) (30 mL) and brine (30 mL).The combined aqueous was extracted with EtOAc (50 mL). The combinedorganics were dried over Na₂SO₄ and concentrated in vacuo to afford 8b.LC/MS (ESI) calculated for C₉H₉Cl₂N₃O: m/z 246.01, found 246.76 [M+H]⁺;t_(R)=0.74 min. on LC/MS Method A.

Synthesis of(R)—N-(2-((7-acetyl-2-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(8c)

To a solution of 8b (550.1 mg, 1.64 mmol) and 1i (360.4 mg, 1.64 mmol)in NMP (6.5 mL) was added N,N-diisopropylethylamine (0.60 mL, 3.29mmol). After stirring at 150° C. for 18 h, the reaction was cooled tort, diluted with EtOAc (30 mL) and washed with water (30 mL). Theaqueous was extracted with EtOAc (30 mL). The Combined organics werewashed with brine (3×50 mL), dried over Na₂SO₄, then filtered andconcentrated in vacuo. The residue was subjected to silica gelchromatography eluting with EtOAc-MeOH to provide 8c as a mixture ofproducts. LC/MS (ESI) calculated for C₁₈H₂₈ClN₅O₂: m/z 382.19, found382.29 [M+H]⁺; t_(R)=0.88 min. on LC/MS Method A.

Synthesis of(R)—N-(2-((7-acetyl-2-((2,4-dimethoxybenzyl)amino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(8d)

To a solution of 8c (173.9 mg, 0.46 mmol) in 2-MeTHF (4.5 mL) was addedpotassium carbonate (131.7 mg, 0.91 mmol) followed by2,4-dimethoxybenzylamine (0.35 mL, 2.28 mmol) in a sealed vessel. Afterstirring at 150° C. for 18 h, the reaction was cooled to rt, dilutedwith EtOAc (30 mL), washed with water (25 mL) and brine (25 mL), driedover Na₂SO₄, then filtered and concentrated in vacuo. The residue waspurified by preparative HPLC (Gemini 10u C18 110A, Axia; 25% aq.acetonitrile-45% aq. acetonitrile, over 15 min. gradient) to provide 8das a TFA salt. LC/MS (ESI) calculated for C₂₇H₄₀N₆O₄: m/z 513.31, found513.41 [M+H]⁺; t_(R)=0.89 min. on LC/MS Method A. ¹H NMR (400 MHz,Chloroform-d) δ 7.93-7.68 (m, 1H), 7.36 (d, J=39.2 Hz, 1H), 7.05 (dd,J=8.3, 4.7 Hz, 1H), 6.45 (dd, J=4.4, 2.3 Hz, 1H), 6.38 (dd, J=8.2, 2.7Hz, 1H), 4.51 (dd, J=12.8, 7.0 Hz, 4H), 3.80 (d, J=6.1 Hz, 3H), 3.78 (d,J=3.4 Hz, 3H), 3.76-3.66 (m, 2H), 3.07 (dd, J=14.6, 6.2 Hz, 1H),2.47-2.29 (m, 2H), 2.21 (s, 3H), 2.13 (d, J=16.1 Hz, 3H), 2.09-2.01 (m,1H), 1.85-1.72 (m, 1H), 1.45 (d, J=2.3 Hz, 3H), 1.32-1.16 (m, 4H), 0.87(td, J=7.0, 3.7 Hz, 3H). ¹⁹F NMR (377 MHz, Chloroform-d) δ −76.44.

Synthesis of(R)—N-(2-((7-acetyl-2-amino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide(8)

To 8d (65.5 mg, 0.13 mmol) was added TFA (3 mL). After 3 h, the reactionmixture was concentrated in vacuo and coevaporated with MeOH (3×20 mL).The residue was suspended in MeOH and filtered. The solution wasconcentrated in vacuo to afford 7 as its TFA salt. LC/MS (ESI)calculated for C₁₈H₃₀N₆O₂: m/z 363.33, found 363.36 [M+H]⁺; t_(R)=0.65min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 7.55 (d, J=23.4Hz, 1H), 4.50 (d, J=1.8 Hz, 2H), 3.93-3.70 (m, 5H), 3.18 (dd, J=14.2,4.7 Hz, 1H), 2.41 (dt, J=38.3, 6.0 Hz, 2H), 2.19 (d, J=12.0 Hz, 3H),2.13-2.05 (m, 1H), 2.01 (d, J=5.8 Hz, 3H), 2.00-1.90 (m, 1H), 1.48 (d,J=3.0 Hz, 3H), 1.41-1.15 (m, 4H), 0.90 (t, J=7.0 Hz, 3H). ¹⁹F NMR (377MHz, Methanol-d₄) δ −77.91.

Example 9

Synthesis of(R)—N-(2-((2-chlorothieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide(9a)

To a solution of 1i (204 mg, 0.98 mmol) and2,4-dichlorothieno[3,2-d]pyrimidine (200 mg, 0.975 mmol, supplied bySynthonix) in 2,4-dioxane (4 mL) was added Na₂CO₃ (420 mg, 3.90 mmol).After stirring at 85° C. for 3 d, the reaction was cooled to rt, dilutedwith EtOAc (20 mL), washed with water (20 mL) and brine (20 mL), driedover Na₂SO₄, then filtered and concentrated in vacuo. The residue wassubjected to silica gel chromatography eluting with hexanes-EtOAc toprovide 9a. LC/MS (ESI) calculated for C₁₅H₂₁ClN₄OS: m/z 341.11, found341.12 [M+H]⁺; t_(R)=1.26 min. on LC/MS Method A. ¹H NMR (400 MHz,Chloroform-d) δ 7.71 (d, J=5.3 Hz, 1H), 7.32 (d, J=5.3 Hz, 1H), 5.72 (s,1H), 3.84 (dd, J=13.9, 5.4 Hz, 1H), 3.70 (dd, J=13.9, 4.8 Hz, 1H), 1.88(td, J=13.1, 11.6, 3.2 Hz, 1H), 1.66 (td, J=14.2, 12.3, 4.4 Hz, 1H),1.35 (s, 3H), 1.31 (tt, J=6.2, 3.3 Hz, 4H), 0.90 (t, J=6.7 Hz, 3H).

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide(9b)

To a solution of 9a (188.7 mg, 0.55 mmol) in 2-MeTHF (4 mL) was addedpotassium carbonate (158 mg, 0.11 mmol) followed by2,4-dimethoxybenzylamine (0.17 mL, 1.11 mmol). After stirring at 85° C.for 18 h, the reaction was cooled to rt, washed with water (10 mL) andbrine (10 mL), dried over Na₂SO₄, then filtered and concentrated invacuo. The residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc to provide 9b. LC/MS (ESI) calculated forC₂₄H₃₃N₅O₃S: m/z 472.23, found 472.23 [M+H]⁺; t_(R)=1.23 min. on LC/MSMethod A. ¹H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J=5.3 Hz, 1H), 7.24(s, 1H), 7.12 (d, J=5.3 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.40 (dd,J=8.2, 2.4 Hz, 1H), 4.57 (dd, J=5.9, 1.5 Hz, 4H), 3.88 (dd, J=14.0, 6.0Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.56 (dd, J=14.1, 5.8 Hz, 1H), 1.92(s, 3H), 1.78 (dq, J=15.1, 8.6, 7.8 Hz, 1H), 1.35 (s, 4H), 1.34-1.25 (m,7H), 0.94-0.86 (m, 3H).

Synthesis of(R)—N-(2-((2-aminothieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide (9)

To 9b (12.9 mg, 0.03 mmol) was added TFA (3 mL). After 2 h, the reactionmixture was concentrated in vacuo and coevaporated with MeOH (3×20 mL).The residue was suspended in MeOH and filtered. The solution wasconcentrated in vacuo to afford 9 as its TFA salt. LC/MS (ESI)calculated for C₁₅H₂₃N₅OS: m/z 322.16, found 322.16 [M+H]⁺; t_(R)=0.92min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.09 (d, J=5.4Hz, 1H), 7.19 (d, J=5.4 Hz, 1H), 4.08 (d, J=13.7 Hz, 1H), 3.77 (d,J=13.7 Hz, 1H), 2.09-2.01 (m, 1H), 1.91 (s, 3H), 1.58-1.47 (m, 1H),1.35-1.29 (m, 4H), 1.28 (s, 3H), 0.92 (t, J=6.8 Hz, 3H). ¹⁹F NMR (377MHz, Methanol-d₄) δ −77.85.

Example 10

Synthesis of tert-butyl (R)-(1-hydroxyhexan-2-yl)carbamate (18a)

To a solution of (R)-norleucinol (4.0 g, 34.1 mmol, supplied by AstatechInc.) in DCM (150 mL) was added di-tert-butyl dicarbonate (14.9 g, 68.3mmol) followed by N,N-diisopropylethylamine (6.0 mL, 34.1 mmol). Afterstirring at 40° C. for 18 h, the reaction was cooled to ambienttemperature, washed with water (75 mL) and brine (75 mL), dried overNa₂SO₄, and concentrated in vacuo. The residue was subjected to silicagel chromatography equipped with an ELSD eluting with hexanes-EtOAc toprovide 10a. LC/MS (ESI) calculated for C₁₁H₂₃NO₃: m/z 218.17, found217.70 [M+H]⁺; t_(R)=0.93 min. on LC/MS Method A. ¹H NMR (400 MHz,Chloroform-d) δ 4.59 (s, 1H), 3.67 (dd, J=10.5, 3.4 Hz, 1H), 3.61 (s,1H), 3.53 (dd, J=10.5, 5.7 Hz, 1H), 2.18 (s, 1H), 1.57-1.47 (m, 1H),1.45 (s, 9H), 1.43-1.38 (m, 1H), 1.39-1.29 (m, 4H), 0.97-0.83 (m, 3H).

Synthesis of tert-butyl(R)-(1-(1,3-dioxoisoindolin-2-yl)hexan-2-yl)carbamate (10b)

To a solution of 10a (7.10 g, 32.1 mmol) in THF (33 mL) was addedtriphenylphosphine (10.5 g, 42.5 mmol), followed by phthalimide (6.3 g,42.5 mmol) and diisopropyl azodicarboxylate (8.4 mL, 425 mmol). Afterstirring at ambient temperature for 18 h, the reaction was diluted withEtOAc (75 mL), washed with water (75 mL) and brine (100 mL), dried overNa₂SO₄, then filtered and concentrated in vacuo. The residue was thentriturated with ether and filtered and concentrated in vacuo severaltimes. The residue was subjected to silica gel chromatography elutingwith hexanes-EtOAc to provide 10b. LC/MS (ESI) calculated forC₁₉H₂₆N₂O₄: m/z 347.19, found 346.37 [M+H]⁺; t_(R)=1.01 min. on LC/MSMethod A. ¹H NMR (400 MHz, Chloroform-d) δ 7.84 (dd, J=5.5, 3.1 Hz, 2H),7.70 (dd, J=5.3, 3.0 Hz, 2H), 4.52 (d, J=9.5 Hz, 1H), 3.97 (s, 1H),3.79-3.53 (m, 2H), 1.64-1.27 (m, 6H), 1.22 (s, 9H), 0.91 (t, J=7.1 Hz,3H).

Synthesis of tert-butyl (R)-(1-aminohexan-2-yl)carbamate (10c)

To a solution of 10b (1.21 g, 3.49 mmol) in EtOH (35 mL) was addedhydrazine monohydrate (0.34 mL, 6.98 mmol). After stirring at 80° C. for18 h, the reaction was cooled to ambient temperature, diluted with ether(50 mL), filtered, rinsed with ether (30 mL), and concentrated in vacuoto yield 10c. ¹H NMR (400 MHz, Chloroform-d) δ 3.52 (s, 1H), 2.78 (dd,J=13.1, 4.5 Hz, 1H), 2.63 (dd, J=13.1, 6.8 Hz, 1H), 1.44 (s, 9H),1.40-1.27 (m, J=3.7 Hz, 6H), 0.89 (t, J=6.3 Hz, 3H).

Synthesis of tert-butyl (R)-(1-acetamidohexan-2-yl)carbamate (10d)

To a solution of 10c (0.68 g, 3.15 mmol) in THF (100 mL) was addedN,N-diisopropylethylamine (0.88 mL, 6.31 mmol) followed by acetylchloride (0.337 mL, 4.72 mmol). After stirring at ambient temperaturefor 1 h, the reaction was diluted with EtOAc (120 mL), washed with sat.sodium bicarbonate solution (150 mL) and brine (75 mL), dried overNa₂SO₄, then filtered and concentrated in vacuo to afford crude 10d.LC/MS (ESI) calculated for C₁₃H₂₆N₂O₃: m/z 259.19, found 258.81 [M+H]⁺;t_(R)=0.90 min. on LC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ3.72-3.50 (m, 1H), 3.30-3.09 (m, 2H), 1.90 (s, 3H), 1.38 (s, 9H),1.34-1.09 (m, 6H), 0.83 (t, J=6.8, 6.1 Hz, 3H).

Synthesis of (R) N-(2-aminohexyl)acetamide (10e)

To a solution of 10d (813 mg, 3.15 mmol) in DCM (6 mL) was added HClsolution (3.2 mL, 4 M in dioxane). After stirring at ambient temperaturefor 18 h, the solution was concentrated in vacuo to afford crude 10e asan HCL salt. LC/MS (ESI) calculated for C₈H₁₈N₂O: m/z 159.14, found159.98 [M+H]⁺; t_(R)=0.49 min. on LC/MS Method A. ¹H NMR (400 MHz,Chloroform-d) δ 3.14-3.04 (m, 1H), 2.10 (s, 3H), 1.80-1.61 (m, 2H),1.29-1.23 (m, 4H), 0.96-0.82 (m, 3H).

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)quinazolin-4-yl)amino)hexyl)acetamide(10g)

To a solution of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) and 10e(107.6 mg, 0.502 mmol) in THF (2 mL) was added N,N-diisopropylethylamine(0.18 mL, 1.0 mmol). After stirring at 75° C. for 18 h,2,4-dimethoxybenzylamine (0.17 mL, 1.1 mmol) was added followed byN,N-diisopropylethylamine (0.20 mL, 1.1 mmol). The reaction was heatedin a microwave reactor at 125° C. for 30 min, the solution was dilutedwith EtOAc (60 mL), washed with water (50 mL) and brine (60 mL), driedof Na₂SO₄, filtered and concentrated in vacuo. The residue was subjectedto silica gel chromatography eluting in hexanes-EtOAc followed byEtOAc-MeOH to provide 10g as an isomeric mixture. LC/MS (ESI) calculatedfor C₂₅H₃₃N₅O₃: m/z 452.26, found 452.37 [M+H]⁺; t_(R)=1.01 min. onLC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ 7.62 (t, J=7.7 Hz, 1H),7.51 (d, J=7.9 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.21 (t, J=9.3 Hz, 1H),7.12 (t, J=7.5 Hz, 1H), 6.44 (d, J=2.3 Hz, 1H), 6.39 (dd, J=8.1, 2.3 Hz,1H), 4.59 (d, J=5.8 Hz, 2H), 4.41-4.13 (m, 1H), 3.84 (d, J=2.8 Hz, 3H),3.77 (d, J=1.5 Hz, 3H), 3.66-3.51 (m, 1H), 3.37 (dt, J=15.0, 4.2 Hz,1H), 1.94 (dd, J=29.2, 2.2 Hz, 3H), 1.75-1.64 (m, 1H), 1.63-1.52 (m,1H), 1.47-1.34 (m, 2H), 1.33-1.28 (m, 2H), 0.90 (dt, J=29.0, 7.1 Hz,3H).

Synthesis of (R)—N-(2-((2-aminoquinazolin-4-yl)amino)hexyl)acetamide(10)

To 10g (67.3 mg, 0.15 mmol) was added TFA (3 mL). After 90 min, thereaction mixture was concentrated in vacuo and coevaporated with MeOH(3×20 mL). The residue was purified by preparative HPLC (Gemini 10u C18110A, Axia; 20% aq. acetonitrile-40% aq. acetonitrile, over 10 min.gradient) to afford 10 as its TFA salt. LC/MS (ESI) calculated forC₁₆H₂₃N₅O: m/z 302.19, found 302.24 [M+H]⁺; t_(R)=0.64 min. on LC/MSMethod A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.03 (dt, J=8.4, 1.0 Hz, 1H),7.77 (ddt, J=8.4, 7.2, 1.1 Hz, 1H), 7.42 (tdd, J=7.2, 2.4, 1.2 Hz, 2H),4.23 (tt, J=9.1, 4.6 Hz, 1H), 3.82 (dd, J=13.4, 4.6 Hz, 1H), 3.58 (dd,J=13.6, 8.4 Hz, 1H), 1.92 (s, 3H), 1.63 (ddt, J=14.0, 9.3, 4.8 Hz, 1H),1.51 (dtd, J=13.8, 9.3, 4.1 Hz, 1H), 1.46-1.28 (m, 4H), 0.93 (t, J=6.6Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d₄) δ −77.86.

Example 11

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoroquinazolin-4-yl)amino)hexyl)acetamide(11b)

To a solution of 2,4-dichloro-7-fluoroquinazoline (100 mg, 0.46 mmol)and 10e (90 mg, 0.46 mmol) in THF (2 mL) was addedN,N-diisopropylethylamine (0.32 mL, 1.8 mmol). After stirring at 75° C.for 18 h, 2,4-dimethoxybenzylamine (0.21 mL, 1.4 mmol) was addedfollowed by N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The reactionwas heated in a microwave reactor at 125° C. for 30 min, diluted withEtOAc (70 mL), washed with water (50 mL) and brine (50 mL), dried ofNa₂SO₄, filtered, and concentrated in vacuo. The residue was subjectedto silica gel chromatography eluting in hexanes-EtOAc followed byEtOAc-MeOH to provide 11b (LC/MS (ESI) calculated for C₂₅H₃₂FN₅O₃: m/z470.25, found 470.34 [M+H]⁺; t_(R)=0.99 min. on LC/MS Method A. ¹H NMR(400 MHz, Chloroform-d) δ 7.55 (dd, J=9.0, 6.0 Hz, 1H), 7.24 (d, J=8.6Hz, 1H), 7.03 (d, J=11.1 Hz, 1H), 6.79 (t, J=8.9 Hz, 1H), 6.45 (d, J=2.3Hz, 1H), 6.40 (dd, J=8.2, 1.9 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 3.83 (s,3H), 3.78 (s, 3H), 3.75-3.68 (m, 1H), 3.62 (d, J=11.3 Hz, 1H), 3.35 (d,J=14.1 Hz, 1H), 1.85 (s, 3H), 1.74-1.64 (m, 1H), 1.64-1.52 (m, 1H),1.40-1.29 (m, 4H), 0.94-0.84 (m, 3H).

Synthesis of(R)—N-(2-((2-amino-7-fluoroquinazolin-4-yl)amino)hexyl)acetamide (11)

To 11b (73.7 mg, 0.16 mmol) was added TFA (3 mL). After 90 min, thereaction mixture was concentrated in vacuo and coevaporated with MeOH(3×20 mL). The residue was purified by preparative HPLC (Gemini 10u C18110A, Axia; 20% aq. acetonitrile-40% aq. acetonitrile, over 10 min.gradient) to afford 11 as its TFA salt. LC/MS (ESI) calculated forC₁₆H₂₂FN₅O: m/z 320.18, found 320.28 [M+H]⁺; t_(R)=0.70 min. on LC/MSMethod A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.10 (dd, J=9.0, 5.4 Hz, 1H),7.18 (ddd, J=18.6, 9.1, 2.5 Hz, 2H), 4.22 (dq, J=12.9, 4.5 Hz, 1H), 3.81(dd, J=13.4, 4.6 Hz, 1H), 3.56 (dd, J=13.4, 8.3 Hz, 1H), 1.92 (s, 3H),1.69-1.56 (m, 1H), 1.56-1.45 (m, 1H), 1.45-1.29 (m, 4H), 0.93 (t, J=7.0Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d₄) δ −77.85, −103.53-104.38 (m).

Example 12

Synthesis of(R)—N-(2-((2-chloro-6,7-difluoroquinazolin-4-yl)amino)hexyl)acetamide(12a)

To a solution of 2,4-dichloro-6,7-difluoroquinazoline (1.00 g, 0.43mmol) and 10e (91 mg, 0.47 mmol) in THF (2.4 mL) was addedN,N-diisopropylethylamine (0.15 mL, 0.85 mmol). After stirring atambient temperature for 18 h, the solution was diluted with EtOAc (75mL), washed with water (50 mL) and brine (60 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to provide crude 12a. LC/MS (ESI)calculated for C₁₆H₁₉ClF₂N₄O: m/z 357.12, found 357.23 [M+H]⁺;t_(R)=1.09 min. on LC/MS Method A. ¹H NMR (400 MHz, Chloroform-d) δ 7.46(dd, J=10.7, 7.6 Hz, 1H), 7.31 (dd, J=15.2, 8.7 Hz, 1H), 4.47-4.30 (m,1H), 3.66 (dt, J=9.2, 2.9 Hz, 1H), 3.39 (ddd, J=14.4, 5.1, 3.1 Hz, 1H),1.99 (s, 3H), 1.74 (t, J=9.0 Hz, 1H), 1.59 (t, J=6.2 Hz, 1H), 1.40-1.31(m, 4H), 0.86-0.77 (m, 3H).

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)-6,7-difluoroquinazolin-4-yl)amino)hexyl)acetamide(12b)

To a solution of 12a (152 mg, 0.43 mmol) in THF (3 mL) was added2,4-dimethoxybenzylamine (0.19 mL, 1.28 mmol) followed byN,N-diisopropylethylamine (0.22 mL, 1.28 mmol). The reaction was heatedin a microwave reactor at 140° C. for 1 h, the solution was diluted withhexanes-EtOAc (1:3, 75 mL), washed with water (2×50 mL) and brine (75mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas subjected to silica gel chromatography eluting in hexanes-EtOAcfollowed by EtOAc-MeOH to provide 12b. LC/MS (ESI) calculated forC₂₅H₃₁F₂N₅O₃: m/z 488.24, found 488.33 [M+H]⁺; t_(R)=1.16 min. on LC/MSMethod A. ¹H NMR (400 MHz, Chloroform-d) δ 7.45 (dt, J=10.8, 7.7 Hz,1H), 7.23 (d, J=8.3 Hz, 1H), 7.18-7.07 (m, 1H), 6.45 (d, J=2.3 Hz, 1H),6.40 (dd, J=8.2, 2.4 Hz, 1H), 4.56 (dd, J=5.9, 3.0 Hz, 2H), 4.41-4.30(m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.56-3.45 (m, 1H), 3.33 (dt,J=14.0, 4.1 Hz, 1H), 1.83 (s, 3H), 1.76-1.61 (m, 1H), 1.60-1.49 (m, 1H),1.36-1.28 (m, 4H), 0.87 (t, J=6.8 Hz, 3H).

Synthesis of(R)—N-(2-((2-amino-6,7-difluoroquinazolin-4-yl)amino)hexyl)acetamide(12)

To 12b (26.0 mg, 0.05 mmol) was added TFA (3 mL). After 90 min, thereaction mixture was concentrated in vacuo and coevaporated with MeOH(3×20 mL. The residue was suspended in MeOH and filtered. The solutionwas concentrated in vacuo to afford 12 as its TFA salt. LC/MS (ESI)calculated for C₁₆H₂₁F₂N₅O: m/z 338.17, found 338.30 [M+H]⁺; t_(R)=0.74min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.21 (dd,J=10.9, 7.9 Hz, 1H), 7.37 (dd, J=10.6, 6.8 Hz, 1H), 4.66 (qd, J=7.4, 4.1Hz, 1H), 3.57 (dd, J=13.9, 4.2 Hz, 1H), 3.30-3.20 (m, 1H), 1.88 (s, 3H),1.70 (pd, J=7.8, 6.9, 3.2 Hz, 2H), 1.46-1.31 (m, 4H), 0.99-0.85 (m, 3H).¹⁹F NMR (377 MHz, Methanol-d₄) δ −77.76, ⁻126.95-⁻128.53 (m), −142.19(ddd, J=21.6, 11.0, 7.0 Hz).

Example 13

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide(13b)

To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (100 mg, 0.49 mmol)and 10a (77 mg, 0.49 mmol) in THF (3 mL) was addedN,N-diisopropylethylamine (0.340 mL, 1.951 mmol). After stirring at 80°C. for 18 h, 2,4-dimethoxybenzylamine (0.293 mL, 1.951 mmol) was addedfollowed by N,N-diisopropylethylamine (0.255 mL, 1.45 mmol). Thereaction was heated in a microwave reactor at 155° C. for 2 h, dilutedwith EtOAc (60 mL) and washed with water (60 mL). The aqueous wasextracted with EtOAc (50 mL), and the combined organic layers werewashed with brine (60 mL), dried over Na₂SO₄, and concentrated in vacuo.The residue was subjected to silica gel chromatography, eluting inhexanes-EtOAc followed by EtOAc-MeOH to provide 13b as an isomericmixture. LC/MS (ESI) calculated for C₂₃H₃₁N₅O₃S: m/z 458.22, found458.30 [M+H]⁺; t_(R)=0.93 min. on LC/MS Method A. ¹H NMR (400 MHz,Chloroform-d) δ 7.56-7.49 (m, 1H), 7.25-7.21 (m, 1H), 7.09 (dd, J=5.4,2.5 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.40 (dd, J=8.2, 2.4 Hz, 1H),4.67-4.46 (m, 2H), 4.45-4.29 (m, 1H), 3.82 (s, 3H), 3.78 (s, 3H),3.75-3.63 (m, 1H), 3.46-3.34 (m, 1H), 1.80 (s, 3H), 1.65-1.43 (m, 2H),1.40-1.29 (m, 4H), 0.94-0.84 (m, 3H).

Synthesis of(R)—N-(2-((2-aminothieno[3,2-d]pyrimidin-4-yl)amino)hexyl)acetamide (13)

To 13b (46.4 mg, 0.10 mmol) was added TFA (3 mL). After 90 min, thereaction mixture was concentrated in vacuo and coevaporated with MeOH(3×20 mL). The residue was purified by preparative HPLC (Gemini 10u C18110A, Axia; 20% aq. acetonitrile-40% aq. acetonitrile, over 10 min.gradient) to afford 13 as its TFA salt. LC/MS (ESI) calculated forC₁₄H₂₁N₅OS: m/z 308.15, found 308.20 [M+H]⁺; t_(R)=0.65 min. on LC/MSMethod A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.07 (d, J=5.4 Hz, 1H), 7.17(d, J=5.4 Hz, 1H), 4.17 (ddt, J=9.5, 7.7, 4.7 Hz, 1H), 3.79 (dd, J=13.5,4.8 Hz, 1H), 3.50 (dd, J=13.5, 7.7 Hz, 1H), 1.91 (s, 3H), 1.60 (ddd,J=13.8, 9.3, 4.5 Hz, 1H), 1.53-1.44 (m, 1H), 1.44-1.27 (m, 5H), 0.92 (t,J=6.9 Hz, 3H). ¹⁹F NMR (377 MHz, Methanol-d₄) δ −77.89.

Example 14

Synthesis of(R)—N-(2-((2-((2,4-dimethoxybenzyl)amino)pteridin-4-yl)amino)-2-methylhexyl)acetamide(14b)

To a solution of 1i (100 mg, 0.58 mmol) and 2,4-dichloropteridine (96mg, 0.58 mmol, supplied by AstaTech, Inc.) in THF (2.5 mL) was addedN,N-diisopropylethylamine (0.25 mL, 1.9 mmol). The mixture was heated ina microwave reactor at 100° C. for 30 min. To the mixture was then added2,4-dimethoxybenzylamine (0.15 mL, 0.96 mmol) and heated in a microwavereactor at 120° C. for 30 min. The reaction was diluted with EtOAc (15mL), washed with water (15 mL) and brine (15 mL), dried over Na₂SO₄,then filtered and concentrated in vacuo. The residue was subjected tosilica gel chromatography eluting with hexanes-EtOAc followed byEtOAc-MeOH to provide 14b. LC/MS (ESI) calculated for C₂₄H₃₃N₇O₃: m/z468.26, found 468.35 [M+H]⁺; t_(R)=0.96 min. on LC/MS Method A. ¹H NMR(400 MHz, Chloroform-d) δ 8.75-8.25 (m, 1H), 8.10 (d, J=14.5 Hz, 1H),7.24 (dd, J=83.8, 8.2 Hz, 1H), 7.08-6.86 (m, 1H), 6.52-6.29 (m, 2H),4.63 (d, J=26.6 Hz, 2H), 3.83 (s, 3H), 3.77 (d, J=8.0 Hz, 3H), 3.74-3.64(m, 2H), 1.95 (d, J=24.8 Hz, 3H), 1.63 (t, J=12.8 Hz, 1H), 1.39 (s, 3H),1.34-1.16 (m, 5H), 0.90-0.81 (m, 3H).

Synthesis of(R)—N-(2-((2-aminopteridin-4-yl)amino)-2-methylhexyl)acetamide (14)

To 14b (52.2 mg, 0.11 mmol) was added TFA (3 mL). After 5 h, thereaction mixture was concentrated in vacuo and coevaporated with MeOH(3×20 mL). The residue was suspended in MeOH and filtered. The solutionwas concentrated in vacuo to afford as its TFA salt. LC/MS (ESI)calculated for C₁₅H₂₃N₇O: m/z 318.20, found 318.45 [M+H]⁺; t_(R)=0.67min. on LC/MS Method A. ¹H NMR (400 MHz, Methanol-d₄) δ 8.77 (d, J=2.4Hz, 2H), 8.65 (d, J=2.3 Hz, 1H), 3.93 (d, J=14.1 Hz, 1H), 3.52 (d,J=14.1 Hz, 1H), 2.25-2.12 (m, 1H), 1.96 (s, 4H), 1.56 (s, 3H), 1.36 (td,J=8.4, 6.9, 4.8 Hz, 4H), 0.96-0.87 (m, 3H).

HPLC Methods

Method for LC/MS HPLC (Method A):

HPLC LC/MS chromatograms were generated using a Thermo Scientific LCQLC/MS system eluting with a Kinetex 2.6u C18 100 A, 5×30 mm HPLC column,using a 1.85 minute gradient elution from 2% aq. acetonitrile-98% aq.acetonitrile with 0.1% formic acid modifier.

Method for LC/MS HPLC (Method B):

HPLC LC/MS chromatograms were generated using a Thermo Scientific LCQLC/MS system eluting with a Kinetex 2.6u C18 100 A, 5×30 mm HPLC column,using a 2.85 minute gradient elution from 2% aq. acetonitrile-98% aq.acetonitrile with 0.1% formic acid modifier.

Cells and Reagents

Cryopreserved human PBMCs isolated from healthy donors were purchasedfrom StemCell Technologies (Vancouver, Canada). Cell culture medium usedwas RPMI with L-Glutamine (Mediatech, Manassas, Va.) supplemented with10% fetal bovine serum (Hyclone, GE Healthcare, Logan, Utah) andPenicillin-Streptomycin (Mediatech). Human TNFα, IL12p40, and IFNα2a384-well Assay capture plates, standards, buffers and processingreagents were obtained from MesoScale Discovery Technologies (MSD;Rockville, Md.).

Cryopreserved human PBMCs (1×10e8 cells/ml) were thawed at 37° C. andresuspended in 25 mL warm cell culture medium. The cells were pelletedat 200×g (Beckman Avanti J-E) for 5 min and resuspended in 20 mL offresh culture media. Cells were counted using a Cellometer (NexcelcomBioscience), adjusted to 2×10e6 cells, and incubated for 2 hours in anincubator set at 37° C., 5% CO₂ to recover from cryopreservation.Compounds were serially diluted in DMSO at half-log steps to generate a10-point dose range. Using a Bravo pipette equipped with a 384 well head(Agilent), 0.4 μL of compound was transferred to each well of a 384 wellblack, clear bottom plate (Greiner Bio-One, Germany) containing 30 μL ofcell culture medium. Recovered PBMCs were then dispensed into the assayplate at 50 μL per well (100 k cells/well) using the MicroFlowmultichannel dispenser (Biotek). Final DMSO concentration was 0.5%. DMSOwas used as the negative control. The plates were incubated for 24 hoursat 37° C. PBMCs in the assay plate were pelleted by centrifugation(Beckman Avanti J-E) at 200×g for 5 min.

Using a Biomek FX 384 well pipetting station (Beckman), conditionedculture medium (CCM) from the assay plate was transferred to MSD captureplates customized for each cytokine. For IFNα and IL12-p40 detection, 25μL and 20 μL of CCM were added directly to each capture plate,respectively. For TNFα detection, CCM was diluted 1:9 in fresh culturemedium, and 20 μL of diluted CCM was used. Serially diluted calibrationstandards for each cytokine were used to generate standard curves andestablish assay linearity. The plates were sealed and incubatedovernight at 4° C. in a plate shaker (Titer Plate) set at 200 rpm. Onthe following day, antibodies specific for each cytokine were diluted1:50 in MSD Diluent 100 antibody dilution buffer. Diluted antibodieswere added to corresponding capture plates at 10 μL/well, and incubatedat RT for 1-2 hrs in the shaker. The plates were washed with PBST buffer(3×, 60 μl/well) using a Biotek Multiflow plate washer. MSD Read Bufferdiluted to 2× in deionized water and 35 μL/well was added via Biomek FXinstrument. The plates were read immediately in a MSD6000 reader. Datawere normalized to positive and negative controls in each assay plate.AC₅₀ values represent compound concentrations at half-maximal effectbased on normalized percent activation and calculated by non-linearregression using Pipeline Pilot software (Accelrys, San Diego, Calif.).

Results of the cytokine profiling assay are reported in Table 1.

Example # TNFa AC₅₀ (nM) IL12p40 AC₅₀ (nM) IFNa AC₅₀ (nM) 1 62.9552.19 >50000 2 40.87 8.83 >50000 3 811.93 703.37 >50000 4 110.35131.73 >50000 5 542.65 363.52 >50000 6 10177 9580.7 >50000 7 24962323.2 >50000 8 4612.3 3628 >50000 9 1100 854.68 >50000 10 16741315 >50000 11 561 433 >50000 12 10192 11998 >50000 13 9519 8288 >5000014 1914 1896 >50000

The present disclosure provides reference to various embodiments andtechniques. However, it should be understood that many variations andmodifications may be made while remaining within the spirit and scope ofthe present disclosure.

What is claimed is:
 1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein: R¹ is —H, C₁₋₄alkyl, or C₁₋₄ haloalkyl; R² is C₁₋₆ alkyl or C₁₋₆ haloalkyl; Q is CR⁴;R³ and R⁴ are taken together to form phenyl optionally substituted with1 to 3 R⁵; each R⁵ is independently halogen, —OH, —NH₂, —CN, C₁₋₄ alkyloptionally substituted with 1 to 3 R^(Z), C₁₋₄ haloalkyl, C₁₋₄ alkoxy,—C(O)OH, —C(O)C₁₋₄ alkyl, —C(O)OC₁₋₄ alkyl, —C(O)NH₂, —C(O)NH(C₁₋₄alkyl), —C(O)N(C₁₋₄ alkyl)₂, —N(H)C(O)C₁₋₄ alkyl, —S(O)₂C₁₋₄ alkyl, or 5to 6 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen,nitrogen, and sulfur optionally substituted with 1 to 3 R^(Z); and eachR^(Z) is independently —NH₂, C₁₋₄ alkyl, halogen, —CN, —OC₁₋₄ alkyl,C₁₋₄ haloalkyl, or —C(O)NH₂.
 2. The compound of claim 1, wherein R¹ is—H or C₁₋₄ alkyl.
 3. The compound of claim 1, wherein R¹ is methyl. 4.The compound of claim 1, wherein R² is C₃₋₆ alkyl.
 5. The compound ofclaim 1, wherein R³ and R⁴ are taken together to form phenyl optionallysubstituted with 1 to 3 chloro, fluoro, bromo, —CN, C₁₋₂ alkyloptionally substituted with —OH, C₁₋₂ alkoxy, —C(O)C₁₋₂ alkyl,—C(O)OC₁₋₂ alkyl, pyrazolyl optionally substituted with 1 to 3 C₁₋₂alkyl; or imidazolyl optionally substituted with 1 to 3 C₁₋₂ alkyl. 6.The compound of claim 1, wherein: R¹ is —H or C₁₋₄ alkyl; R² is C₃₋₆alkyl; R³ and R⁴ are taken together to form phenyl optionallysubstituted with 1 to 3 halogen.
 7. The compound of claim 1, whereinFormula I is represented by Formula II


8. The compound of claim 1, wherein Formula I is represented by FormulaIII


9. The compound of claim 6, wherein R³ and R⁴ are taken together to formphenyl optionally substituted with 1 to 3 fluoro.
 10. The compound ofclaim 1, selected from

or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.12. The pharmaceutical composition of claim 11, further comprising oneor more additional therapeutic agents.
 13. A kit comprising a compoundof claim 1, or a pharmaceutically acceptable salt thereof.